Inhibitors of cellular metabolic processes

ABSTRACT

The present disclosure provides MAT2A inhibitor compounds that are useful as therapeutic agents for treating malignancies, and wherein the compounds conform to general formula (IA): 
                         
wherein R A , R B , R C , R D , and R E  are defined herein.

CLAIM FOR PRIORITY

This application is a continuation of U.S. application Ser. No.15/691,408, filed Aug. 30, 2017, which claims the benefit of priority toU.S. Application Ser. No. 62/548,738, filed Aug. 22, 2017, and is also acontinuation-in-part of International Patent Application Serial No.PCT/CN2016/097524, filed Aug. 31, 2016, the contents of which are eachincorporated herein by reference in their entireties.

FIELD OF THE DISCLOSURE

The present disclosure relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors of MAT2Aenzyme which are useful for treating certain cancers.

BACKGROUND

Methionine adenosyltransferase (MAT) also known as S-adenosylmethioninesynthetase is a cellular enzyme that catalyzes the synthesis ofS-adenosyl methionine (SAM or AdoMet) from methionine and ATP and isconsidered the rate-limiting step of the methionine cycle. SAM is thepropylamino donor in polyamine biosynthesis and the principal methyldonor for DNA methylation and is involved in gene transcription andcellular proliferation as well as the production of secondarymetabolites.

Two genes, MAT1A and MAT2A, encode two distinct catalytic MAT isoforms.A third gene, MAT2B, encodes a MAT2A regulatory subunit. MAT1A isspecifically expressed in the adult liver, whereas MAT2A is widelydistributed. Because MAT isoforms differ in catalytic kinetics andregulatory properties, MAT1A-expressing cells have considerably higherSAM levels than do MAT2A-expressing cells. It has been found thathypomethylation of the MAT2A promoter and histone acetylation causesupregulation of MAT2A expression.

In hepatocellular carcinoma (HCC), the downregulation of MAT1A and theup-regulation of MAT2A occur, which is known as the MAT1A:MAT2A switch.The switch, accompanied with up-regulation of MAT2B, results in lowerSAM contents, which provide a growth advantage to hepatoma cells.Because MAT2A plays a crucial role in facilitating the growth ofhepatoma cells, it is a target for antineoplastic therapy. Recentstudies have shown that silencing by using small interfering RNAsubstantially suppresses growth and induces apoptosis in hepatoma cells.See, e.g., T. Li et al., J. Cancer 7(10) (2016) 1317-1327.

It has been reported by Marjon et al (Cell Reports 15(3) (2016) 574-587)that cancer cell lines that are MTAP deficient are particularlysensitive to inhibition of MAT2A. MTAP (methylthioadenosinephosphorylase) is an enzyme widely expressed in normal tissues thatcatalyzes the conversion of methylthioadenosine (MTA) into adenine and5-methylthioribose-1-phosphate. The adenine is salvaged to generateadenosine monophosphate, and the 5-methylthioribose-1-phosphate isconverted to methionine and formate. Because of this salvage pathway,MTA can serve as an alternative purine source when de novo purinesynthesis is blocked, e.g., with antimetabolites, such as L-alanosine.

Many human and murine malignant cells lack MTAP activity. MTAPdeficiency is not only found in tissue culture cells but the deficiencyis also present in primary leukemias, gliomas, melanomas, pancreaticcancers, non-small cell lung cancers (NSLC), bladder cancers,astrocytomas, osteosarcomas, head and neck cancers, myxoidchondrosarcomas, ovarian cancers, endometrial cancers, breast cancers,soft tissue sarcomas, non-Hodgkin lymphomas, and mesotheliomas. The geneencoding for human MTAP maps to region 9p21 on human chromosome 9p. Thisregion also contains the tumor suppressor genes p16INK4A (also known asCDKN2A), and p15INK4B. These genes code for p16 and p15, which areinhibitors of the cyclin D-dependent kinases cdk4 and cdk6,respectively.

The p16INK4A transcript can alternatively be ARF spliced into atranscript encoding p14ARF. p14ARF binds to MDM2 and preventsdegradation of p53 (Pomerantz et al. (1998) Cell 92:713-723). The 9p21chromosomal region is of interest because it is frequently homozygouslydeleted in a variety of cancers, including leukemias, NSLC, pancreaticcancers, gliomas, melanomas, and mesothelioma. The deletions ofteninactivate more than one gene. For example, Cairns et al. ((1995) Nat.Gen. 11:210-212) reported that after studying more than 500 primarytumors, almost all the deletions identified in such tumors involved a170 kb region containing MTAP, p14ARF and P16INK4A. Carson et al (WO99/67634) reported that a correlation exists between the stage of tumordevelopment and loss of homozygosity of the gene encoding MTAP and thegene encoding p16. For example, deletion of the MTAP gene, but notp16INK4A was reported to be indicative of a cancer at an early stage ofdevelopment, whereas deletion of the genes encoding for p16 and MTAP wasreported to be indicative of a cancer at a more advanced stage of tumordevelopment. Garcia-Castellano et al reported that in some osteosarcomapatients, the MTAP gene was present at diagnosis but was deleted at alater time point (Garcia-Castellano et al., supra).

SUMMARY

For the reasons above, the present disclosure satisfies a significantneed for safe and effective compounds and methods for treating,preventing and managing cancers while reducing or avoiding thetoxicities and/or side effects associated with the conventionaltherapies. The cancers include those that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy.

In accordance with some embodiments, the present disclosure provides acompound according to formula IA or a pharmaceutically acceptable saltthereof:

In Formula IA, R^(A) is selected from the group consisting of H,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₃-C₁₄-carbocycle,(C₃-C₁₄-carbocyclo)-C₁-C₆-alkyl-, 3- to 14-membered heterocycle orheterocyclo-C₁-C₆-alkyl- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S), (3- to 14-memberedheterocyclo)oxy-, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-,C₆-C₁₄-aryloxy-, —(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R², —NR¹R², —C(O)NR¹R²,NR¹C(NR²)NR¹R², NR¹C(NR²)(═NR¹), SR¹, —CN, and —OH. Each alkyl, alkenyl,alkoxy, aryl, and heterocycle is optionally substituted with one or moresubstituents selected from the group consisting of R¹, OR¹, halo,—N═N—R¹, NR¹R², —(C₁-C₆-alkyl)NR¹R², —C(O)OR¹, —C(O)NR¹R², —OC(O)R¹,—CN, —OP(O)(OR¹)₁₋₂, and oxo.

R^(B) is selected from the group consisting of H, C₂-C₆-alkenyl, andC₁-C₆-alkyl, wherein R^(B) is optionally substituted by one or more R¹.

R^(C), R^(D), and R^(E) are independently selected from the groupconsisting of C₃-C₁₄-carbocycle, C₆-C₁₄-aryl, and 3- to 14-memberedheterocycle (wherein 1 to 4 heterocycle ring members are heteroatomsselected from N, O, and S). R^(C), R^(D), and R^(E) are optionallysubstituted with one or more substituents selected from the groupconsisting of R¹, —OR¹, halo, —NR¹R², —(C₁-C₆-alkyl)-NR¹R², —C(O)OR¹,—C(O)NR¹R², —NO₂, —CN, and oxo.

R¹ and R² are independently selected from the group consisting of H, D(²H), —CN, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, NH₂,C₂-C₆-alkynyl, —S(O)₀₋₂—(C₁-C₆-alkyl), —S(O)₀₋₂—(C₆-C₁₄-aryl),—C(O)(C₁-C₆-alkyl), —C(O)(C₃-C₁₄-carbocyclo), —C₃-C₁₄-carbocycle,C₆-C₁₄-aryl, 3- to 14-membered heterocycle or heterocyclo(C₁-C₆-alkyl)-(wherein 1 to 4 heterocycle ring members are heteroatoms selected fromN, O, and S).

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocyclemoiety of R¹ and R² is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy, halo, —NH₂,—NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH, —C(O)O(C₁-C₆-alkyl),—C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl, —C(O)C₁-C₆-alkyl,—OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃, C₆-C₁₄-aryl,—(C₁-C₆-alkyl)(C₆-C₁₄-aryl), 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S), and —O(C₆-C₁₄-aryl).

In another embodiment, there is provided a pharmaceutical compositioncomprising s compound of formula (IA) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

Another embodiment is a method for treating a disease or conditionmediated by the overexpression of MAT2A in a mammal in need thereof,comprising administering to the mammal an effective amount of a compoundof formula (IA) or a pharmaceutically acceptable salt thereof.

Yet another embodiment is a method of treating an MTAP null cancer in asubject comprising administering to the subject an effective amount of acompound of formula (IA) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present disclosure provides a method forinhibiting the synthesis of S-adenosyl methionine (SAM) from methionineand ATP by MAT2A in a cell, comprising contacting the cell with aneffective amount of a compound of formula (IA) or a pharmaceuticallyacceptable salt thereof.

Also provided in an embodiment is a method for treating a cancer in asubject suffering therefrom, wherein the cancer is characterized by areduction or absence of methylthioadenosine phosphorylase (MTAP) geneexpression, the absence of the MTAP gene, or reduced function of MTAPprotein, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (IA) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present disclosure provides a compound offormula (IA) or a pharmaceutically acceptable salt thereof, forinhibiting the synthesis of S-adenosyl methionine (SAM) from methionineand ATP by MAT2A in a cell.

In still another embodiment, there is provided a compound of formula(IA) or a pharmaceutically acceptable salt thereof, for treating adisease or condition in a subject suffering therefrom, wherein thedisease or condition is mediated by the overexpression of MAT2A.

Yet another embodiment provides a compound of formula (IA) or apharmaceutically acceptable salt thereof, for treating a cancer in asubject suffering therefrom, wherein the cancer is characterized by areduction or absence of methylthioadenosine phosphorylase (MTAP) geneexpression, the absence of the MTAP gene, or reduced function of MTAPprotein.

DETAILED DESCRIPTION

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), andheteroaroyl.

“Alkyl” means a branched or unbranched, saturated or unsaturated (i.e.alkenyl, alkynyl) aliphatic hydrocarbon group, in an embodiment, havingup to 12 carbon atoms unless otherwise specified, such as a C₁-C₆-alkyl.When used as part of another term, for example “alkylamino”, the alkylportion may be a saturated hydrocarbon chain, but also includesunsaturated hydrocarbon carbon chains such as “alkenylamino” and“alkynylamino. Examples of particular alkyl groups are methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl,2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. Theterms “lower alkyl” “C₁-C₄ alkyl” and “alkyl of 1 to 4 carbon atoms” aresynonymous and used interchangeably to mean methyl, ethyl, 1-propyl,isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-butyl. Unless specified,substituted alkyl groups may contain one, for example two, three or foursubstituents which may be the same or different, and are chosen, unlessotherwise specified, from halogen (F, Cl, Br, I), hydroxy, protectedhydroxy, cyano, nitro, alkoxy (for example C₁-C₆ alkoxy), benzyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl,heterocyclyl sulfonylamino, heterocyclylsulfonylaminoalkyl,heterocyclyl, aryl, or other groups specified.

“Amino” means primary (i.e. —NH₂), secondary (i.e. —NRH) and tertiary(i.e. —NRR) amines in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl.Particular secondary and tertiary amines are alkylamine, dialkylamine,arylamine, diarylamine, aralkylamine and diaralkylamine wherein thealkyl is as herein defined and optionally substituted. Particularsecondary and tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine,dipropylamine and disopropylamine.

“Aryl” when used alone or as part of another term means a carbocyclicaromatic group whether or not fused having the number of carbon atomsdesignated or if no number is designated, up to 14 carbon atoms, such asa C₆-C₁₄-aryl. Particular aryl groups are phenyl, naphthyl, biphenyl,phenanthrenyl, naphthacenyl, and the like (see e.g. Lang's Handbook ofChemistry (Dean, J. A., ed) 13^(th) ed. Table 7-2 [1985]). A particulararyl is phenyl. Substituted phenyl or substituted aryl means a phenylgroup or aryl group substituted with one, two, three, four or five, forexample 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified,from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro,alkyl (for example C₁-C₆ alkyl), alkoxy (for example C₁-C₆ alkoxy),benzyloxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, trifluoromethyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl,heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl,aryl, or other groups specified. One or more methyne (CH) and/ormethylene (CH₂) groups in these substituents may in turn be substitutedwith a similar group as those denoted above. Examples of the term“substituted phenyl” includes but is not limited to a mono- ordi(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl,4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like;a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl,3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; acyanophenyl group, for example, 4-cyanophenyl; a mono- or di(loweralkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl,2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyland the like; a mono or di(alkoxy)phenyl group, for example,3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such 4-carboxyphenyl; a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenylgroups where the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Particularsubstituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl,2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl,4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Fused aryl rings may also be substituted with any, for example1, 2 or 3, of the substituents specified herein in the same manner assubstituted alkyl groups.

“Carbocyclyl”, “carbocyclylic”, “carbocycle” and “carbocyclo” alone andwhen used as a moiety in a complex group such as a carbocycloalkylgroup, refers to a mono-, bi-, or tricyclic carbon ring having 3 to 14carbon atoms, for example 3 to 7 carbon atoms, which may be saturated,unsaturated, partially unsaturated, aromatic (aryl) or non-aromatichaving the number of atoms designated, generally from 5 to about 14 ringatoms. Particular saturated carbocyclic groups are cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl groups. A particular saturatedcarbocycle is cyclopropyl. Another particular saturated carbocycle iscyclohexyl. Particular unsaturated carbocycles are aromatic e.g. arylgroups as previously defined, for example phenyl. Particular partiallyunsaturated carbocyclic groups are cyclobutene, cyclopentene,cyclohexene and cycloheptene. The terms “substituted carbocyclyl”,“carbocycle” and “carbocyclo” mean these groups substituted by the samesubstituents as the “substituted alkyl” group unless specifiedotherwise.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” alone and when used as a moiety in a complex group such asa heterocycloalkyl group, are used interchangeably and refer to anymono-, bi-, or tricyclic, saturated, unsaturated, partially unsaturated,aromatic (heteroaryl) or non-aromatic ring having the number of atomsdesignated, generally from 5 to about 14 ring atoms, where the ringatoms are carbon and at least one heteroatom (nitrogen, sulfur oroxygen), for example 1 to 4 heteroatoms. Typically, a 5-membered ringhas 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 doublebonds and the nitrogen or sulfur heteroatoms may optionally be oxidized(e.g. SO, SO₂), and any nitrogen heteroatom may optionally bequaternized. Particular non-aromatic heterocycles are morpholinyl(morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl,tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl,piperazinyl and piperidinyl. A “heterocycloalkyl” group is a heterocyclegroup as defined above covalently bonded to an alkyl group as definedabove. Particular 5-membered heterocycles containing a sulfur or oxygenatom and one to three nitrogen atoms are thiazolyl, in particularthiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for exampleoxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and1,2,4-oxadiazol-5-yl. Particular 5-membered ring heterocycles containing2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl;triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl,1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Particularbenzo-fused 5-membered heterocycles are benzoxazol-2-yl,benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-memberedheterocycles contain one to three nitrogen atoms and optionally a sulfuror oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl,such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides andpyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl groups, are a particular group.Substituents for “optionally substituted heterocycles”, and furtherexamples of the 5- and 6-membered ring systems discussed above can befound in W. Druckheimer et al., U.S. Pat. No. 4,278,793. In a particularembodiment, such optionally substituted heterocycle groups aresubstituted with one or more of hydroxyl, alkyl, alkoxy, acyl, halogen,mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano,nitro, amidino, and guanidino.

“Heteroaryl” alone and when used as a moiety in a complex group such asa heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromaticring system having the number of atoms designated where at least onering is a 5-, 6- or 7-membered ring containing from one to fourheteroatoms selected from the group nitrogen, oxygen, and sulfur, and ina particular embodiment at least one heteroatom is nitrogen (Lang'sHandbook of Chemistry, supra). Included in the definition are anybicyclic groups where any of the above heteroaryl rings are fused to abenzene ring. Particular heteroaryls incorporate a nitrogen or oxygenheteroatom. The following ring systems are examples of the heteroaryl(whether substituted or unsubstituted) groups denoted by the term“heteroaryl”: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. A particular “heteroaryl” is:1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-ylsodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl,4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide,6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl. An alternative group of“heteroaryl” includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionallysubstituted as described for heterocycles.

“Inhibitor” means a compound which prevents or reduces the amount ofsynthesis of S-adenosylmethionine (SAM) from methionine and ATP byMAT2A. In an embodiment, an inhibitor binds to MAT2A.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g. 2, 3 or 4) ofthe substituents listed for that group in which said substituents may bethe same or different. In an embodiment, an optionally substituted grouphas 1 substituent. In another embodiment an optionally substituted grouphas 2 substituents. In another embodiment an optionally substitutedgroup has 3 substituents.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. In an embodiment, compounds of the present disclosure are in theform of a pharmaceutically acceptable salt. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like. “Pharmaceutically acceptable base additionsalts” include those derived from inorganic bases such as sodium,potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper,manganese, aluminum salts and the like. Particularly base addition saltsare the ammonium, potassium, sodium, calcium and magnesium salts. Saltsderived from pharmaceutically acceptable organic nontoxic bases includessalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine,arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, methylglucamine, theobromine, purines,piperizine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly organic non-toxic bases are isopropylamine,diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline,and caffeine. In an embodiment the compound of the present disclosure isa salt. In an embodiment, the compound of the present disclosure is apharmaceutically acceptable salt. In an embodiment, the compound of thepresent disclosure is an acetate. In an embodiment, the compound of thepresent disclosure is a benzoate salt. In an embodiment, the compound ofthe present disclosure is a besylate salt. In an embodiment, thecompound of the present disclosure is a bitartrate salt. In anembodiment, the compound of the present disclosure is a bromide salt. Inan embodiment, the compound of the present disclosure is a carbonatesalt. In an embodiment, the compound of the present disclosure is achloride salt. In an embodiment, the compound of the present disclosureis a citrate salt. In an embodiment, the compound of the presentdisclosure is an edetate salt. In an embodiment, the compound of thepresent disclosure is an edisylate salt. In an embodiment, the compoundof the present disclosure is a estolate salt. In an embodiment, thecompound of the present disclosure is a fumerate salt. In an embodiment,the compound of the present disclosure is a gluceptate salt. In anembodiment, the compound of the present disclosure is a gluconate salt.In an embodiment, the compound of the present disclosure is ahydrobromide salt. In an embodiment, the compound of the presentdisclosure is a hydrochloride salt. In an embodiment, the compound ofthe present disclosure is an iodide salt. In an embodiment, the compoundof the present disclosure is a lactate salt. In an embodiment, thecompound of the present disclosure is a lactobionate salt. In anembodiment, the compound of the present disclosure is a malate salt. Inan embodiment, the compound of the present disclosure is a maleate salt.In an embodiment, the compound of the present disclosure is a madelatesalt. In an embodiment, the compound of the present disclosure is amesylate salt. In an embodiment, the compound of the present disclosureis a methyl bromide salt.

In an embodiment, the compound of the present disclosure is a methylsulfate salt. In an embodiment, the compound of the present disclosureis a napsylate salt. In an embodiment, the compound of the presentdisclosure is a nitrate salt. In an embodiment, the compound of thepresent disclosure is a pamoate salt. In an embodiment, the compound ofthe present disclosure is a phosphate salt. In an embodiment, thecompound of the present disclosure is a disphosphate salt. In anembodiment, the compound of the present disclosure is a salicylate salt.In an embodiment, the compound of the present disclosure is adisalicylate salt. In an embodiment, the compound of the presentdisclosure is a stearate salt. In an embodiment, the compound of thepresent disclosure is a succinate salt. In an embodiment, the compoundof the present disclosure is a sulfate salt. In an embodiment, thecompound of the present disclosure is a tartrate salt. In an embodiment,the compound of the present disclosure is a tosylate salt. In anembodiment, the compound of the present disclosure is a triethiodidesalt. In an embodiment, the compound of the present disclosure is avalerate salt. In an embodiment, the compound of the present disclosureis an aluminum salt. In an embodiment, the compound of the presentdisclosure is a benzathine salt. In an embodiment, the compound of thepresent disclosure is a calcium salt. In an embodiment, the compound ofthe present disclosure is a ethylenediamine salt. In an embodiment, thecompound of the present disclosure is a lysine salt. In an embodiment,the compound of the present disclosure is a magnesium salt. In anembodiment, the compound of the present disclosure is a meglumine salt.In an embodiment, the compound of the present disclosure is a potassiumsalt. In an embodiment, the compound of the present disclosure is aprocaine salt. In an embodiment, the compound of the present disclosureis a sodium salt. In an embodiment, the compound of the presentdisclosure is a tromethamine salt. In an embodiment, the compound of thepresent disclosure is a zinc salt.

Compounds of the present disclosure may exist in different tautomericforms. In an embodiment, the compounds are in the form as drawn ornamed. In another embodiment, the compounds are in a tautomeric formother than as drawn or named. Compounds of the present disclosure mayexist as one or a mixture of salts and solvate forms. For example acompound of the present disclosure may be substantially pure in oneparticular salt or solvate form or else may be mixtures of two or moresalt or solvate forms. In an embodiment, the compounds are in solvateform. In a particular embodiment, the compounds exist as hydrates.

Compounds

As described generally above, the present disclosure provides compoundsand pharmaceutically acceptable salts thereof, wherein the compoundsconform to formula (IA):

In Formula IA, R^(A) is selected from the group consisting of H,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₃-C₁₄-carbocycle,(C₃-C₁₄-carbocyclo)-C₁-C₆-alkyl-, 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S), (3- to 14-memberedheterocyclo)oxy-, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-,C₆-C₁₄-aryloxy-, —(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R², NR¹R², C(O)NR¹R²,NR¹C(NR²)NR¹R², NR¹C(NR²)(═NR¹), SR¹, —CN, and —OH. Each alkyl, alkenyl,alkoxy, aryl, and heterocycle is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹,OR¹, halo, —N═N—R¹, NR¹R², —(C₁-C₆-alkyl)NR¹R², —C(O)OR¹, —C(O)NR¹R²,—OC(O)R¹, —CN, —OP(O)(OR¹)₁₋₂, and oxo.

R^(B) is selected from the group consisting of H, C₂-C₆-alkenyl, andC₁-C₆-alkyl, wherein R^(B) is optionally substituted by one or more R¹;

R^(C), R^(D), and R^(E) are independently selected from the groupconsisting of C₃-C₁₄-carbocycle, C₆-C₁₄-aryl, and 3- to 14-memberedheterocycle (wherein 1 to 4 heterocycle ring members are heteroatomsselected from N, O, and S). R^(C), R^(D), and R^(E) are optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹, —OR¹, halo, —NR¹R², —(C₁-C₆-alkyl)-NR¹R²,—C(O)OR¹, —C(O)NR¹R², —NO₂, —CN, and oxo.

R¹ and R² are independently selected from the group consisting of H, D(²H), —CN, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, NH₂,C₂-C₆-alkynyl, —S(O)₀₋₂—(C₁-C₆-alkyl), —S(O)₀₋₂—(C₆-C₁₄-aryl),—C(O)(C₁-C₆-alkyl), —C(O)(C₃-C₁₄-carbocyclo), —C₃-C₁₄-carbocycle,C₆-C₁₄-aryl, 3- to 14-membered heterocycle or heterocyclo(C₁-C₆-alkyl)-(wherein 1 to 4 heterocycle ring members are heteroatoms selected fromN, O, and S).

Each R¹ and R² is optionally substituted with one or more substituentsindependently selected from the group consisting of hydroxy, halo, —NH₂,—NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH, —C(O)O(C₁-C₆-alkyl),—C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl, —C(O)C₁-C₆-alkyl,—OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃, C₆-C₁₄-aryl,—(C₁-C₆-alkyl)(C₆-C₁₄-aryl), 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S), and —O(C₆-C₁₄-aryl). Each alkyl,aryl, and heterocyclo in R¹ and R² is optionally substituted with one ormore substituents independently selected from the group consisting ofhydroxy, —OC₁-C₆-alkyl, halo, —NH₂, —(C₁-C₆-alkyl)NH₂, —C(O)OH, CN, andoxo.

In some embodiments of Formula IA compounds, R^(D) and R^(E) areindependently selected from C₃-C₁₄-carbocycle, C₆-C₁₄-aryl, and 3- to14-membered heterocycle (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S). More specifically, R^(D) andR^(E) are independently selected from C₃-C₁₄-carbocycle and C₆-C₁₄-aryl,or C₅-C₇-carbocycle and C₆-C₁₀-aryl. In exemplary embodiments, R^(D) andR^(E) are independently selected from cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, and phenyl. For instance, one of R^(D) andR^(E) is cyclohexyl or cyclohexenyl and the other is phenyl.

In other embodiments, optionally in combination with any otherembodiment described herein, R^(A) is selected from the group consistingof C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₃—C₁₄-carbocycle,(C₃-C₁₄-carbocyclo)-C₁-C₆-alkyl-, 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S), C₆-C₁₄-aryl,(C₆-C₁₄-aryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy, —(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R²,NR¹R², NR¹C(NR²)NR¹R², —CN, and —OH. Substituents R¹ and R² have themeanings described herein above for Formula IA.

Various other embodiments provide a Formula IA compound wherein R^(A) isselected from the group consisting of H, OH, NH₂, CN, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl-, NC—C₁-C₆-alkyl-, —C₁-C₆-alkyl-NH(C₁-C₆-alkyl),NH₂—C₁-C₆-alkyl-, —(CH₂)₀₋₁—NH—C(O)R² (where R² is NH₂, C₁-C₆-alkyloptionally substituted with one or more substituents independentlyselected from halo, hydroxy-C₁-C₆-alkyl-, 3- to 14-membered heterocycleoptionally substituted with one or more of C₁-C₆-alkyl and oxo, andC₃-C₁₄-carbocycle), —NHR² (wherein R² is 3- to 14-membered heterocycleoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹, OR¹, halo, —N═N—R¹, NR¹R²,—(C₁-C₆-alkyl)NR¹R², —C(O)OR¹, —OC(O)R¹, —CN, —OP(O)(OR¹)₁₋₂, and oxo),—C(O)NR¹R² (wherein R¹ and R² are independently H, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl-, 3- to 14-membered heterocyclo-C₁-C₆-alkyl-,C₆-C₁₄-aryloxy-, or (3- to 14-membered heterocyclo)oxy-).

In some embodiments, R^(A) is selected from the group consisting ofC₁-C₆-alkyl, —(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R², NR¹R², and NR¹C(NR²)NR¹R². Forexample, R^(A) can be C₁-C₆-alkyl or NR¹R². In exemplary embodiments,R^(A) is NR¹R². Some Formula IA compounds, in accordance with variousembodiments, have R^(A) as a secondary amino group, i.e., R^(A) isNR¹R², where R¹ is H and R² is as defined hereinabove.

In various embodiments, some Formula IA compounds conform to Formula IB:

In Formula IB compounds and pharmaceutically acceptable salts thereof,according to various embodiments, R^(C) is a C₃-C₁₄-carbocycle or a 3-to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, and S). R^(C) is optionally substitutedwith one or more substituents selected from the group consisting ofhydroxy, halogen, —NH₂, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-,carboxy, —CN, oxo, C₁-C₆-alkyl, C₁-C₆-alkoxy, and —NH(C₁-C₆-alkyl). TheC₁-C₆-alkyl, C₁-C₆-alkoxy, and NH(C₁-C₆-alkyl) are independently andoptionally substituted with one or more of hydroxy, halogen, —NH₂,carboxy, —CN, and oxo.

Substituents R^(D) and R^(E) are independently a C₃-C₁₄-carbocycle or a3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring membersare heteroatoms selected from N, O, and S). R^(D) and R^(E) areoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, —NH₂, C₆-C₁₄-aryl,(C₆-C₁₄-aryl)-C₁-C₆-alkyl-, carboxy, —CN, oxo, C₁-C₆-alkyl,C₁-C₆-alkoxy, and —NH(C₁-C₆-alkyl). The C₁-C₆-alkyl, C₁-C₆-alkoxy, andNH(C₁-C₆-alkyl) are independently and optionally substituted with one ormore of hydroxy, halogen, —NH₂, carboxy, —CN, and oxo.

Substituent R¹ is selected from the group consisting of H, C₁-C₆-alkyl,C₃-C₁₄-carbocycle, and 3- to 14-membered heterocycle (wherein 1 to 4heterocycle ring members are heteroatoms selected from N, O, and S). R¹is optionally substituted with one or more substituents selected fromthe group consisting of hydroxy, halogen, —NH₂, —NO₂, —CN, oxo, carboxy,—C(O)OC₁-C₆-alkyl, (C₁-C₆-alkyl)OC₁-C₆-alkyl-, —C(O)NH₂, C₁-C₆-alkyl,—C(O)H, C₁-C₆-alkoxy, (C₁-C₆-alkyl)N(H)-aryl-,(C₆-C₁₄-aryl)C₁-C₆-alkyl-, 5- to 7-membered heteroaryl, (5- to7-membered heteroaryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy,(C₆-C₁₄-aryl)(C₁-C₆-alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5-to 7-membered heteroaryl)(C₁-C₆-alkoxy)-. The C₁-C₆-alkyl, C₁-C₆-alkoxy,(C₁-C₆-alkyl)N(H)—, —C(O)OC₁-C₆-alkyl, (C₁-C₆-alkyl)OC₁-C₆-alkyl-,—C(O)NH₂, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)C₁-C₆-alkyl-, 5- to 7-memberedheteroaryl, (5- to 7-membered heteroaryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy,(C₆-C₁₄-aryl)(C₁-C₆-alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5-to 7-membered heteroaryl)(C₁-C₆-alkoxy)-, are optionally substitutedwith one or more of hydroxy, halogen, —NH₂, (C₁-C₆-alkyl)N(H)—, —COOH,—CN, and oxo. Further, each heteroaryl in R¹ has 1 to 4 heteroaryl ringmembers that are heteroatoms selected from N, O, and S.

In some Formula IB compounds, according to various embodiments, R^(D) isC₃-C₁₄-carbocycle optionally substituted with one or more members of thegroup consisting of hydroxy, halogen, —NH₂, —C(O)OH, —CN, oxo, alkyl,C₁-C₆-alkyl, C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)—. The C₁-C₆-alkyl,C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)— are optionally substituted with oneor more of hydroxy, halogen, —NH₂, —C(O)OH, —CN, and oxo.

Some embodiments provide Formula IB compounds wherein R^(D) is phenyl.In other embodiments, R^(D) is cyclohex-1-en-1-yl.

In other Formula IB compounds, in accordance with additionalembodiments, R^(E) is C₃-C₁₄-carbocycle optionally substituted with oneor more members of the group consisting of hydroxy, halogen, —NH₂,—C(O)OH, —CN, oxo, alkyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)—. The C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)— are optionally substituted with one or more ofhydroxy, halogen, —NH₂, —C(O)OH, —CN, and oxo.

Specific examples of R^(E) include but are not limited to a memberselected from the group consisting of cyclohex-1-en-1-yl,(²H₉)cyclohex-1-en-1-yl, cyclohexan-1,3-dien-1-yl,4,4-difluorocyclohex-1-en-1-yl, cyclopent-1-en-1yl, cyclopentyl,pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin-3-yl, pyridin-2-yl,1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl,5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl,1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and3,6-dihydro-2H-pyran-4-yl.

For example, in some Formula IB compounds R^(E) is phenyl. Optionally incombination with this embodiment, R^(D) is cyclohex-1-en-1-yl.

In another embodiment, R^(D) or R^(E) is phenyl optionally substituted,such as with one or more groups consisting of halogen, amino, hydroxyand alkoxy. For instance, R^(D) or R^(E) is phenyl substituted with oneor more groups consisting of F, Cl, NH₂ and OH. In a particularembodiment ring R^(D) is phenyl, such as 2-fluorophenyl, 3-fluorophenyl,3-chlorophenyl, 4-aminophenyl, or 4-hydroxyphenyl.

In other embodiments concerning Formula IB, R^(C) is C₃-C₁₄-carbocycleor 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ringmembers are heteroatoms selected from N, O, and S) and that isoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, —NH₂, —C(O)OH, —CN, oxo,C₁-C₆-alkyl, C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)—. The C₁-C₆-alkyl,C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)— are optionally substituted withhydroxy, halogen, —NH₂, —C(O)OH, —CN and oxo.

In various embodiments, R^(D) is a carbocycle or a heterocycle eachoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, NH₂, carboxy, CN, oxo, alkyl,alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino areoptionally substituted with hydroxy, halogen, NH₂, carboxy, CN and oxo.In one embodiment, R^(D) is an optionally substituted carbocycle that issaturated or partially unsaturated. The carbocycle is optionallysubstituted with one or more members of the group consisting of hydroxy,halogen, NH₂, carboxy, CN, oxo, alkyl, alkoxy and alkylamino whereinsaid alkyl, alkoxy and alkylamino are optionally substituted withhydroxy, halogen, NH₂, carboxy, CN and oxo. In another embodiment, thesaturated or partially unsaturated carbocycle is substituted with one ormore halogen, such as one or two F. More specific examples of R^(D)include optionally substituted cyclohex-1-en-yl and a saturated orpartially unsaturated ring that is deuterated. In a particularembodiment, the ring is fully deuterated. Illustrative examples of R^(D)include cyclohex-1-en-1-yl (E), (²H₉)cyclohex-1-en-1-yl,cyclohexa-E,Z-1,3-dien-1-yl, 4,4-difluorocyclohex-1-en-1-yl,cyclopent-E1-en-1yl, and cyclopentyl.

In some embodiments R^(D) is a heterocycle optionally substituted withone or more substituents selected from the group consisting of hydroxy,halogen, NH₂, carboxy, CN, oxo, alkyl, alkoxy and alkylamino whereinsaid alkyl, alkoxy and alkylamino are optionally substituted withhydroxy, halogen, NH₂, carboxy, CN and oxo. For example, the heterocycleis aromatic, i.e. heteroaryl. Examples include pyridyl, such aspyridin-3-yl or pyridin-2-yl. Other examples include pyrazolyl,4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl,4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z),3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl,tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and3,6-dihydro-2H-pyran-4-yl.

In other embodiments, R^(D) is a non-aromatic heterocycle that isoptionally substituted with one or more halogen or alkoxy. For instance,the halogen is one or two F.

In other embodiments, R^(D) is a deuterated heterocycle. In oneembodiment, the heterocycle is fully deuterated. In a particularembodiment, R^(D) is piperidin-1-yl, such as (²H₁₀)piperidin-1-yl.

In various embodiments R^(E) is a carbocycle or a heterocycle eachoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, NH₂, carboxy, CN, oxo, alkyl,alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino areoptionally substituted with hydroxy, halogen, NH₂, carboxy, CN and oxo.In a particular embodiment R^(E) is phenyl, such as 2-fluorophenyl,3-fluorophenyl, 3-chlorophenyl, 4-aminophenyl, and 4-hydroxyphenyl. Inan embodiment, R^(E) is a saturated or partially unsaturated carbocyclethat is optionally substituted with one or more members of the groupconsisting of hydroxy, halogen, NH₂, carboxy, CN, oxo, alkyl, alkoxy andalkylamino wherein said alkyl, alkoxy and alkylamino are optionallysubstituted with hydroxy, halogen, NH₂, carboxy, CN or oxo. In someembodiments, the saturated or partially unsaturated carbocycle issubstituted with one or more halogen, such as one or two F. Forinstance, R^(E) is optionally substituted cyclohex-1-en-yl, or is asaturated or partially unsaturated ring that is partially or fullydeuterated. Illustrative examples of R^(E) include cyclohex-1-en-1-yl(E), (²H₉)cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3-dien-1-yl,4,4-difluorocyclohex-1-en-1-yl, cyclopent-E1-en-1yl, and cyclopentyl.

In other embodiments R^(E) is a heterocycle optionally substituted withone or more substituents selected from the group consisting of hydroxy,halogen, NH₂, carboxy, CN, oxo, alkyl, alkoxy and alkylamino whereinsaid alkyl, alkoxy and alkylamino are optionally substituted withhydroxy, halogen, NH₂, carboxy, CN and oxo. In an embodiment, theheterocycle is aromatic, i.e. heteroaryl, including pyridyl such aspyridin-3-yl and pyridin-2-yl. In some embodiments the heteroaryl ispyrazole, 4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, or 1H-pyrrol-3-yl.

In an embodiment, R^(E) is a non-aromatic heterocycle that is optionallysubstituted with one or more halogen or alkoxy. For instance, in oneembodiment where R^(E) is substituted by halogen, the halogen is one ortwo F. In other embodiments, the heterocycle is deuterated, such asfully deuterated. Illustrative examples of R^(E) include piperidin-1-yl,(²H₁₀)piperidin-1-yl, 4,4-difluoropiperidin-1-yl,5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4-yl,1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl,3,3-difluoropyrrolidin-1-yl, and 3,6-dihydro-2H-pyran-4-yl.

In other embodiments, R^(D) and R^(E) are the same as defined herein. Inan embodiment ring A and ring B are both phenyl. In an embodiment, ringA and ring B are different and are as defined herein. In an embodiment,ring A is phenyl and ring B is selected from the group consisting of2-fluorophenyl, 3-fluorophenyl, 4-aminophenyl, 4-hydroxyphenyl,4-methoxypyridin-3-yl, pyridin-2-yl, 1H-pyrazol-4-yl,3,6-dihydro-2H-pyran-4-yl, and 1H-pyrrol-3-yl. In an embodiment, ring Bis phenyl and ring A is selected from the group consisting of2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, piperidin-1-yl,(²H₁₀)piperidin-1-yl, 4,4-difluoropiperidin-1-yl, cyclohex-1-en-1-yl(E), (²H₉)cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3-dien-1-yl,4,4-difluorocyclohex-1-en-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z),3,6-dihydro-2H-pyran-4-yl, cyclopentyl, cyclopent-E1-en-1yl,1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, and3,3-difluoropyrrolidin-1-yl.

In various embodiments, R^(E) is phenyl and R^(D) is cyclohex-1-en-1-yl(E). Other R^(E)/R^(D) combinations are contemplated in additionalembodiments, such as phenyl/2-fluorophenyl, phenyl/3-fluorophenyl,phenyl/3-chlorophenyl, phenyl/piperidin-1-yl,phenyl/(²H₁₀)piperidin-1-yl, phenyl/4,4-difluoropiperidin-1-yl,phenyl/cyclohex-1-en-1-yl (E), phenyl/(²H₉)cyclohex-1-en-1-yl,phenyl/cyclohexa-E,Z-1,3-dien-1-yl,phenyl/4,4-difluorocyclohex-1-en-1-yl, phenyl/5,6-dihydro-2H-pyran-3-yl(Z), phenyl/3,6-dihydro-2H-pyran-4-yl, phenyl/cyclopentyl,phenyl/cyclopent-E1-en-1yl, phenyl/1H-pyrrol-3-yl,phenyl/1H-pyrrol-1-yl, phenyl/tetrahydrofuran-3-yl,phenyl/3,3-difluoropyrrolidin-1-yl, and pyridin-2-yl/phenyl.

As described more generally above, in accordance with variousembodiments, R^(C) is a carbocycle or a heterocycle each optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy,alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or aheterocycle wherein the alkyl, alkoxy, alkylamino, acyl, acylamino,acyloxy, cycloalkoxy, carbocycle and heterocycle are optionallysubstituted with hydroxy, halogen, NH₂, carboxy, CN, oxo, a carbocycleor a heterocycle wherein the carbocycle and heterocycle are optionallysubstituted with one or more OH, oxo, amino, halo and haloalkyl. Inadditional embodiments, R^(C) is a carbocycle or a heterocycle eachoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl,alkoxy and alkylamino wherein the alkyl, alkoxy and alkylamino areoptionally substituted with hydroxy, halogen, amino, carboxy, CN andoxo. Alternatively, R^(C) is a carbocycle optionally substituted withone or more substituents selected from the group consisting of hydroxy,halogen, amino, carboxy, CN, oxo, phosphate, sulfate, alkyl, alkoxy,alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or aheterocycle wherein the alkyl, alkoxy, alkylamino, acyl, acylamino,acyloxy, cycloalkoxy, carbocycle and heterocycle are optionallysubstituted with hydroxy, halogen, NH₂, carboxy, CN, oxo, phosphate,sulfate, a carbocycle or a heterocycle wherein the carbocycle andheterocycle are optionally substituted with one or more OH, oxo, amino,halo and haloalkyl. For example, the optionally substituted carbocycleis aromatic, i.e. aryl, optionally substituted with one or moresubstituents selected from the group consisting of OH, amino, halogen,alkyl, alkoxy and cycloalkoxy wherein the alkyl, alkoxy, cycloalkoxy areoptionally substituted with one or more OH, halogen, amino, oxo, acarbocycle or heterocycle wherein the carbocycle and heterocycle areoptionally substituted with one or more hydroxy, halogen, oxo, alkyl andhaloalkyl. In one embodiment, the aryl group, such as phenyl, isoptionally substituted with OH, halogen, alkoxy, amino, haloalkoxy,aminoethoxy and hydroxyethoxy. Specific examples of R^(C) include phenyloptionally substituted with a substituent selected from OH, F, Cl,methyl, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,dimethylaminoethoxy, 2-hydroxyethoxy and phosphate.

In various embodiments, R^(C) is selected from the group consisting of3-hydroxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, 4-ethoxyphenyl, 4-trifluoromethoxyphenyl,4-hydroxy-2-methylphenyl, 4-hydroxy-2-methoxyphenyl,3,4-dihydroxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl,4-(2-(dimethylamino)ethoxy)phenyl, 3-fluoro-4-hydroxyphenyl,3-fluoro-4-methoxyphenyl, 2-chloro-4-hydroxyphenyl,2-fluoro-4-methoxyphenyl, 3-amino-4-hydroxyphenyl,3-amino-4-fluorophenyl, 3-(N,N-dimethylaminoethoxy)-4-hydroxyphenyl,3-chloro-2-hydroxyphenyl, 3-hydroxyethoxy-4-hydroxyphenyl,

In still other embodiments, R^(C) is a heterocycle optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, halogen, amino, carboxyl, CN, oxo, phosphate,sulfate, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy,cycloalkoxy, a carbocycle or a heterocycle wherein the alkyl, alkoxy,alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle andheterocycle are optionally substituted with one or more hydroxy,halogen, NH₂, carboxy, CN, oxo, phosphate, sulfate, a carbocycle or aheterocycle wherein said carbocycle and heterocycle are optionallysubstituted with OH, oxo, amino, halo and haloalkyl. For example, theheterocycle is aromatic, such as a heteroaryl optionally substitutedwith one or more substituents selected from the group consisting of OH,amino, halogen, alkyl, alkoxy and cycloalkoxy wherein said alkyl, alkoxyand cycloalkoxy are optionally substituted with one or more OH, halogen,amino, oxo, a carbocycle or heterocycle wherein said carbocycle andheterocycle are optionally substituted with hydroxy, halogen, oxo, alkyland haloalkyl. In some embodiments, R^(C) is a heteroaryl groupoptionally substituted with one or more OH, amino, alkyl, carboxyl,alkyl, alkoxy and cycloalkoxy wherein the alkyl is optionallysubstituted with OH, amino, oxo, alkoxy, a heterocycle optionallysubstituted with oxo and wherein the cycloalkoxy is optionallysubstituted with OH. Specific examples of R^(C) include6-methoxypyridin-3-yl, 2-methoxypyridin-4-yl, 1H-pyrazol-4-yl,quinolin-6-yl, 2-methylquinolin-6-yl, 2-methoxyquinolin-6-yl,2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl,2-aminoquniazolin-6-yl, 4-aminoquinazolin-6-yl, cinnolin-6-yl,quinoxalin-6-yl, 2-chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl,3-aminoquinoxalin-6-yl, 3-hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl, orimidazo[1,2-a]pyridin-6-yl.

In other embodiments, R^(C) is selected from the group consisting of6-methoxypyridin-3-yl, 2-methoxypyridin-4-yl, 1H-pyrazol-4-yl,quinolin-6-yl, 2-methylquinolin-6-yl, 2-methoxyquinolin-6-yl,2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl,2-aminoquniazolin-6-yl, 4-aminoquinazolin-6-yl, cinnolin-6-yl,quinoxalin-6-yl, 2-chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl,3-aminoquinoxalin-6-yl, 3-hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl,imidazo[1,2-a]pyridin-6-yl,

Alternatively, illustrative Formula IB compounds provide for R^(C) as4-methoxyphenyl.

In various embodiments, R¹ is H or alkyl, a carbocycle or a heterocycleeach optionally substituted with one or more substituents selected fromthe group consisting of hydroxy, halogen, NH₂, NO₂, carboxy,alkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl,alkoxy and alkylamino, and wherein the alkyl, alkoxy, alkylamino,alkoxycarbonyl, alkoxyalkyl and alkylaminocarbonyl are optionallysubstituted with hydroxy, halogen, amino, alkylamino, carboxy, CN andoxo. In one embodiment, R₁ is alkyl optionally substituted with one ormore substituents selected from the group consisting of hydroxy,halogen, NH₂, NO₂, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo,alkyl, acyl, alkoxy and alkylamino wherein the alkyl, alkoxy,alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionallysubstituted with hydroxy, halogen, NH₂, alkylamino, carboxy, CN and oxo.In another embodiment, R₁ is alkyl substituted with OH and oxo. Invarious other embodiments, R₁ is hydroxyethanoyl; a carbocycleoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, NH₂, NO₂, carboxy, alkoxycarbonyl,alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino whereinsaid alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl areoptionally substituted with hydroxy, halogen, NH₂, alkylamino, carboxy,CN and oxo; or a heterocycle optionally substituted with one or moresubstituents selected from the group consisting of hydroxy, halogen,NH₂, NO₂, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl,acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino,alkoxycarbonyl, alkylaminocarbonyl are optionally substituted withhydroxy, halogen, NH₂, alkylamino, carboxy, CN and oxo. In accordancewith some embodiments, the optionally substituted heterocycle ispyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl,1,2,4-triazinyl, pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl or1,2,4-triazin-3-yl. In an embodiment, R¹ is pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, 1,3,5-triazinyl or 1,2,4-triazinyl each ofwhich is optionally substituted with one or more F, Cl, CN, OH, NO₂,NH₂, NHMe —C(O)NH₂ and methoxy. In an embodiment the substituent is F,Cl, CN or OH. In another embodiment, the optionally substitutedheterocycle is pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl or1,2,4-triazin-3-yl each of which is optionally substituted with one ormore F, Cl, CN, OH, NO₂, NH₂, NHMe —C(O)NH₂ and methoxy. In anembodiment the substituent is F, Cl, CN or OH.

According to various embodiments, optionally in combination with anyother embodiments described herein, the present disclosure provides forFormula IB compounds wherein R¹ is selected from a 3- to 14-memberedheterocycle optionally substituted with one or more substituentsselected from the group consisting of hydroxy, halogen, —NH₂, —NO₂,—C(O)OH, —C(O)OC₁-C₆-alkyl, (C₁-C₆-alkyl)N(H)C(O)—, —CN, oxo,C₁-C₆-alkyl, —C(O)H, C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)—. TheC₁-C₆-alkyl, C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)—, C(O)OC₁-C₆-alkyl, and(C₁-C₆-alkyl)N(H)C(O)— are optionally substituted with one or more ofhydroxy, halogen, —NH₂, (C₁-C₆-alkyl)N(H)—, —C(O)H, —CN, and oxo.

In more specific embodiments, R¹ is selected from the group consistingof pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,each of which is optionally substituted with one or more of F, Cl, CN,OH, —NO₂, —NH₂, —NHMe, —C(O)NH₂, and methoxy.

Illustrative moieties for R¹ are selected from the group consisting of:

In an embodiment, R₁ is a 5-member heterocycle optionally substitutedwith OH, amino, alkyl, alkoxy and alkoxyalkyl wherein said alkyl, alkoxyand alkoxyalkyl are optionally substituted with one or more OH, oxo,amino, alkoxy and acyloxy. For example, R¹ is imidazole, pyrazolyl,isoxazole, thiazolyl, 4,5-dihydrothiazolyl, 1H-1,2,4-triazolyl,2H-1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl optionally substituted withOH, amino, alkyl, alkoxy, alkoxyalkyl, wherein the alkyl, alkoxy andalkoxyalkyl groups are optionally substituted with OH, oxo and amino.

Alternatively, in accordance with other embodiments, R¹ isimidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, pyrazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, 4,5-dihydrothiazol-2-yl,1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 1,3,4-oxadiazol-2-yl,1,2,5-oxadiazol-3-yl, 1,2,4-thiadiazol-5-yl or 1,3,4-thiadiazol-2-yloptionally substituted with OH, amino, alkyl, alkoxy, alkoxyalkyl,wherein the alkyl, alkoxy and alkoxyalkyl groups are optionallysubstituted with OH, oxo and amino.

Specific examples of R¹ are selected from the group consisting of:

The present disclosures also provides compounds having the generalformula I:

wherein ring A and ring B are independently a carbocycle or aheterocycle each optionally substituted with one or more substituentsselected from the group consisting of hydroxy, halogen, amino, carboxy,CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy andalkylamino are optionally substituted with hydroxy, halogen, amino,carboxy, CN and oxo;

In this embodiment, ring C is is a carbocycle or a heterocycle eachoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl,alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycleor a heterocycle wherein said alkyl, alkoxy, alkylamino, acyl,acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle areoptionally substituted with hydroxy, halogen, NH₂, carboxy, CN, oxo, acarbocycle or a heterocycle wherein said carbocycle and heterocycle areoptionally substituted with OH, oxo, amino, halo and haloalkyl;

R₁ is H or alkyl, a carbocycle or a heterocycle each optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, halogen, amino, NO₂, CN, oxo, carboxy,alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, alkyl, acyl, alkoxy,alkylamino aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy,heteroaryloxy and heteroaralkoxy wherein said alkyl, alkoxy, alkylamino,alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aryl, aralkyl, heteroaryl,heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy areoptionally substituted with hydroxy, halogen, amino, alkylamino,carboxy, CN or oxo.

Compounds of the present disclosure may also comprise one or moreisotopic substitutions. For example, H may be in any isotopic form,including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be inany isotopic form, including ¹¹C, ¹²C, ¹³C, and ¹⁴C; N may be in anyisotopic form, including ¹³N, ¹⁴N and ¹⁵N; O may be in any isotopicform, including ¹⁵O, ¹⁶O and ¹⁸O; F may be in any isotopic form,including ¹⁸F; and the like. For example, the compound is enriched in aspecific isotopic form of H, C, N, O and/or F by at least about 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. Such compoundsmay be referred to as “isotopologues” and may be useful of the methodsof treatment disclosed herein or may be useful in assays for detectionof the compound, for example, in competition assays to test othernon-isotope containing compounds. In an embodiment, compounds of thepresent disclosure comprise an isotope. In an embodiment the isotope isdeuterium.

Specific compounds conforming to formula IA, or pharmaceuticallyacceptable salts thereof, include those in Table 1 below:

TABLE 1

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Specific compounds conforming to formula IB, or pharmaceuticallyacceptable salts thereof, include those of Table 2:

TABLE 2

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The present disclosure also encompasses prodrugs of the compoundsdescribed above. Suitable prodrugs where applicable include knownamino-protecting and carboxy-protecting groups which are released, forexample hydrolyzed, to yield the parent compound under physiologicconditions. A particular class of prodrugs are compounds in which anitrogen atom in an amino, amidino, aminoalkyleneamino,iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH)group, an alkylcarbonyl (—CO—R′″) group, an alkoxycarbonyl (—CO—OR′″),an acyloxyalkyl-alkoxycarbonyl (—CO—O—R′″—O—CO—R′″) group where R′″ is amonovalent or divalent group and as defined above or a group having theformula —C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same ordifferent and are H, lower alkyl, lower alkoxy, cyano, halo, lower alkylor aryl. In a particular embodiment, the nitrogen atom is one of thenitrogen atoms of the amidino group of the compounds of the presentdisclosure. These prodrug compounds are prepared reacting the compoundsof the present disclosure described above with an activated acylcompound to bond a nitrogen atom in the compound of the presentdisclosure to the carbonyl of the activated acyl compound. Suitableactivated carbonyl compounds contain a good leaving group bonded to thecarbonyl carbon and include acyl halides, acyl amines, acyl pyridiniumsalts, acyl alkoxides, in particular acyl phenoxides such asp-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, anddifluorophenoxy acyl. The reactions are generally exothermic and arecarried out in inert solvents at reduced temperatures such as −78 toabout 50° C. The reactions are usually also carried out in the presenceof an inorganic base such as potassium carbonate or sodium bicarbonate,or an organic base such as an amine, including pyridine, triethylamine,etc. One manner of preparing prodrugs is described in WO 9846576, thecontent of which is incorporated herein by reference in its entirety.

Compounds of the present disclosure may exist in different resonanceforms and that all such resonance forms are within the scope of thepresent disclosure herein.

Compounds of the present disclosure are prepared using standard organicsynthetic techniques from commercially available starting materials andreagents. It will be appreciated that synthetic procedures employed inthe preparation of compounds of the present disclosure will depend onthe particular substituents present in a compound and that variousprotection and deprotection steps that are standard in organic synthesismay be required but may not be illustrated in the following generalschemes.

In a particular embodiment, compounds of the present disclosureconforming to formula IB may be prepared by the general Scheme 1.

In step A of scheme 1, acetate starting material a incorporating R^(C)is reacted with dimethyl carbonate in presence of a suitable strongbase, such as potassium t-butoxide, to provide dimethyl malonateintermediate b, which is reacted in a suitable solvent such as xylenewith intermediate c, 1H-pyrazol-5-amine substituted with R^(D) andR^(E), to provide the 5-hydroxy substituted pyrazolopyrimidoneintermediate d incorporating rings R^(C), R^(D), and R^(E). The5-hydroxy group is then converted to the chloro intermediate e byreacting with phosphoryl chloride which also converts the 7-keto groupto a chloro. The 7-chloro group is converted to a methoxy group in stepD by reacting intermediate e with sodium methoxide to give intermediatef which is then aminated at the 5-position of the pyrazolopyrimidonering in step E by reacting with the amine intermediate g in the presenceof a palladium catalyst to give intermediate h. Finally, the 7-methoxygroup is hydrolyzed to a ketone in step F to give the final product offormula (IB).

Aminopyrazole intermediate c from scheme 1 may be prepared usingstandard organic synthetic techniques from commercially availablestarting materials and reagents. Scheme 2 illustrates a generalprocedure for preparing the intermediate.

Acetonitrile intermediate m incorporating R^(D) is reacted with ester nincorporating R^(E) with an appropriate base catalyst such as sodiumhexamethyldisilazide to form 3-oxo-propanenitrile intermediate ocontaining both R^(D) and R^(E). This is then reacted with hydrazinehydrate to form 5-aminopyrazolo intermediate c which may be used inscheme 1 to prepare compounds of the present disclosure.

In an aspect of the present disclosure, there is provided a process forpreparing a compound of formula IA or IB

wherein R^(C), R^(D), R^(E), and R₁ are as defined herein, comprisinghydrolyzing a compound of formula h

There is provided a process for preparing a compound of formula h

comprising reacting a compound having the formula f

wherein X is a halogen, with an amine of formula g

wherein R₁ is as defined herein.

In an embodiment, X is Cl. In an embodiment, the reaction is catalyzedwith a palladium complex, such as a palladium-Xantphos complex. Forinstance, the reaction is catalyzed with Pd(OAc)₂-Xantphos complex. Inone embodiment, the reaction is performed in dioxane solvent.

In another embodiment, there is provided a process for preparing acompound of formula f

comprising reacting a compound of formula e

with sodium methoxide. In an embodiment the reaction is performed inmethanol.

In an embodiment, there is provided a process for preparing a compoundof formula e

comprising reacting a compound of formula d

with phosphoryl chloride. In an embodiment, the reaction is heated.

In an embodiment, there is provided a process for preparing a compoundof formula d

comprising reacting a compound of formula c

with a compound of formula b

In an embodiment, there is provided a process for preparing a compoundof formula b

comprising reacting a compound of formula a

with dimethyl carbonate.Methods of Use

The MAT2A enzyme catalyzes the synthesis of S-adenosyl methionine (SAM)from methionine and ATP in cells. Accordingly, in another aspect of thepresent disclosure there is provided a method of inhibiting in a cellthe synthesis of SAM from methionine and ATP comprising introducing intosaid cell an effective amount of a compound of formula IA or IB or asalt thereof. In another aspect of the present disclosure, compounds offormula IA or IB may be used to identify other compounds that areinhibitors of MAT2A, for example, in a competition assay for binding toMAT2A or for the inhibition of SAM production. Binding to MAT2A or theinhibition of SAM production by a test compound having a detectablelabel can be measured with and without the presence of an unlabeledcompound of the present disclosure.

Overexpression of the enzyme MAT2A has been demonstrated to mediatecertain cancers. Accordingly, in an aspect of the present disclosurethere is provided a method for treating a cancer mediated by theoverexpression of MAT2A comprising contacting said cancer with aneffective amount of a compound of formula IA or IB or a pharmaceuticallyacceptable salt thereof. In another aspect of the present disclosurethere is provided a method for treating a disease or condition mediatedby the overexpression of MAT2A in a mammal, comprising administering tosaid mammal an effective amount of a compound of formula IA or IB or apharmaceutically acceptable salt thereof. In an embodiment, the canceris neuroblastoma, intestine carcinoma such as rectum carcinoma, coloncarcinoma, familiarly adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma,larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary glandcarcinoma, gastric carcinoma, adenocarcinoma, medullary thyroideacarcinoma, papillary thyroidea carcinoma, renal carcinoma, kidneyparenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpuscarcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchialcarcinoma, small cell lung carcinoma, non-small cell lung carcinoma,multiple myeloma, basalioma, teratoma, retinoblastoma, choroideamelanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma,chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma andplasmocytoma. In an embodiment, the cancer is lung cancer, non-smallcell lung (NSLC) cancer, bronchioloalviolar cell lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, gastriccancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, mesothelioma, hepatocellular cancer, biliarycancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms ofthe central nervous system (CNS), spinal axis tumors, brain stem glioma,glioblastoma multiforme, astrocytomas, schwannomas, ependymomas,medulloblastomas, meningiomas, squamous cell carcinomas, pituitaryadenomas, including refractory versions of any of the above cancers, ora combination of one or more of the above cancers. Methylthioadenosinephosphorylase (MTAP) is an enzyme found in all normal tissues thatcatalyzes the conversion of methylthioadenosine (MTA) into adenine and5-methylthioribose-1-phosphate. The adenine is salvaged to generateadenosine monophosphate, and the 5-methylthioribose-1-phosphate isconverted to methionine and formate. Because of this salvage pathway,MTA can serve as an alternative purine source when de novo purinesynthesis is blocked, e.g., with antimetabolites, such as L-alanosine.Many human and murine malignant cells lack MTAP activity. MTAPdeficiency is not only found in tissue culture cells but the deficiencyis also present in primary leukemias, gliomas, melanomas, pancreaticcancers, non-small cell lung cancers (NSLC), bladder cancers,astrocytomas, osteosarcomas, head and neck cancers, myxoidchondrosarcomas, ovarian cancers, endometrial cancers, breast cancers,soft tissue sarcomas, non-Hodgkin lymphomas, and mesotheliomas. It hasbeen reported by K. Marjon et al., Cell Reports 15 (2016) 574-587,incorporated herein by reference, that proliferation of cancer cellsthat are MTAP null is inhibited by knocking down MAT2A expression withshRNA which was confirmed using small molecule inhibitors of MAT2A suchas those of the present disclosure. An MTAP null cancer is a cancer inwhich the MTAP gene has been deleted or lost or otherwise deactivated ora cancer in which the MTAP protein has a reduced or impaired function.

Accordingly, in an embodiment of the present disclosure there isprovided a method for treating an MTAP null cancer in a subject whereinsaid cancer is characterized by a reduction or absence of MTAPexpression or absence of the MTAP gene or reduced function of MTAPprotein as compared to cancers where the MTAP gene is present and fullyfunctioning, said method comprising administering to the subject atherapeutically effective amount of a compound of formula IA or IB or apharmaceutically acceptable salt thereof. In another embodiment, thereis provided a method of treating an MTAP null cancer in a subjectcomprising administering to the subject an effective amount of acompound of formula IA or IB or a pharmaceutically acceptable saltthereof. In an embodiment, the MTAP null cancer is leukemia, glioma,melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer,astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma,ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma,non-Hodgkin lymphoma or mesothelioma. In an embodiment, the MTAP nullcancer is pancreatic cancer. In an embodiment, the MTAP null cancer isbladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer,breast cancer, esophageal cancer, head and neck cancer, kidney cancer,colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblasticleukemia (ALL) or mantle cell lymphoma (MCL). In an embodiment, the MTAPnull cancer is pancreatic cancer. In an embodiment, the MTAP null canceris gastric cancer. In an embodiment, the cancer is colon cancer. In anembodiment, the MTAP null cancer is liver cancer. In an embodiment, theMTAP null cancer is glioblastoma multiforme (GBM). In an embodiment, theMTAP null cancer is bladder cancer. In an embodiment, the MTAP nullcancer is esophageal cancer. In an embodiment, the MTAP null cancer isbreast cancer. In an embodiment, the MTAP null cancer is NSLCC. In anembodiment, the MTAP null cancer is MCL. In an embodiment, the MTAP nullcancer is DLBCL. In an embodiment, the MTAP null cancer is ALL.

Genomic analysis of MTAP null cell lines revealed that in cell linesthat also incorporate a KRAS mutation or a p53 mutation were sensitiveto MAT2A inhibition. Accordingly, one aspect of the present disclosureprovides a method for treating a cancer in a subject wherein said canceris characterized by reduction or absence of MTAP expression or absenceof the MTAP gene or reduced function of MTAP protein, said methodcomprising administering to the subject a therapeutically effectiveamount of a compound of formula IA or IB, wherein said cancer is furthercharacterized by the presence of mutant KRAS or mutant p53. In anotheraspect of the present disclosure there is provided a method of treatingan MTAP null cancer having a mutant KRAS or mutant p53 in a subject,comprising administering to the subject an effective amount of acompound of formula IA or IB or a pharmaceutically acceptable saltthereof. In an embodiment, the cancer is MTAP null and KRAS mutant. Inan embodiment, the cancer is MTAP null and p53 mutant. In an embodiment,the cancer is MTAP null, KRAS mutant and p53 mutant.

The term “mutant KRAS” or “KRAS mutation” refers to KRAS proteinincorporating an activating mutation that alters its normal function andthe gene encoding such a protein. For example, a mutant KRAS protein mayincorporate a single amino acid substitution at position 12 or 13. In aparticular embodiment, the KRAS mutant incorporates a G12X or G13Xsubstitution, wherein X represents any amino acid change at theindicated position. In a particular embodiment, the substitution isG12V, G12R, G12C or G13D. In another embodiment, the substitution isG13D. By “mutant p53” or “p53 mutation” is meant p53 protein (or geneencoding said protein) incorporating a mutation that inhibits oreliminates its tumor suppressor function. In an embodiment, said p53mutation is, Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S,C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C,R282W, A159V or R280K. In an embodiment, the foregoing cancer isnon-small cell lung cancer (NSLCC), pancreatic cancer, head and neckcancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.

The compounds may be administered prior to, concomitantly with, orfollowing administration of radiation therapy or cytostatic orantineoplastic chemotherapy. Suitable cytostatic chemotherapy compoundsinclude, but are not limited to (i) antimetabolites, such as cytarabine,fludarabine, 5-fluoro-2′-deoxyuiridine, gemcitabine, hydroxyurea ormethotrexate; (ii) DNA-fragmenting agents, such as bleomycin, (iii)DNA-crosslinking agents, such as chlorambucil, cisplatin,cyclophosphamide or nitrogen mustard; (iv) intercalating agents such asadriamycin (doxorubicin) or mitoxantrone; (v) protein synthesisinhibitors, such as L-asparaginase, cycloheximide, puromycin ordiphtheria toxin; (Vi) topoisomerase I poisons, such as camptothecin ortopotecan; (vii) topoisomerase II poisons, such as etoposide (VP-16) orteniposide; (viii) microtubule-directed agents, such as colcemid,colchicine, paclitaxel, vinblastine or vincristine; (ix) kinaseinhibitors such as flavopiridol, staurosporin, STI571 (CPG 57148B) orUCN-01 (7-hydroxystaurosporine); (x) miscellaneous investigationalagents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH₃, orfarnesyl transferase inhibitors (L-739749, L-744832); polyphenols suchas quercetin, resveratrol, piceatannol, epigallocatechine gallate,theaflavins, flavanols, procyanidins, betulinic acid and derivativesthereof; (xi) hormones such as glucocorticoids or fenretinide; (xii)hormone antagonists, such as tamoxifen, finasteride or LHRH antagonists.In a particular embodiment, compounds of the present disclosure arecoadministered with a cytostatic compound selected from the groupconsisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.In a particular embodiment, the cytostatic compound is doxorubicin.

In another embodiment, compounds of the present disclosure may be usedalone as an immuno-oncology therapy or in combination with animmuno-oncology therapy. In an embodiment, the compound of the presentdisclosure is administered prior to, concomitantly with, or followingadministration of an immune checkpoint inhibitor. In an embodiment, thecheckpoint inhibitor is a PD-1 inhibitor. In an embodiment, thecheckpoint inhibitor is a PD-L1 inhibitor. In an embodiment, thecheckpoint inhibitor is ipilimumab. In an embodiment, the checkpointinhibitor is pembrolizumab, nivolumab, or atezolizumab.

The compounds of the present disclosure can be also used in combinationwith radiation therapy. The phrase “radiation therapy” refers to the useof electromagnetic or particulate radiation in the treatment ofneoplasia. Radiation therapy is based on the principle that high-doseradiation delivered to a target area will result in the death ofreproducing cells in both tumor and normal tissues. The radiation dosageregimen is generally defined in terms of radiation absorbed dose (rad),time and fractionation, and must be carefully defined by the oncologist.The amount of radiation a patient receives will depend on variousconsideration but the two most important considerations are the locationof the tumor in relation to other critical structures or organs of thebody, and the extent to which the tumor has spread.

Examples of radiotherapeutic agents are provided in, but not limited to,radiation therapies known in the art (Hellman, Principles of RadiationTherapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devitaet al., 4th ed., vol 1, 1993). Recent advances in radiation therapyinclude three-dimensional conformal external beam radiation, intensitymodulated radiation therapy (IMRT), stereotactic radiosurgery andbrachytherapy (interstitial radiation therapy), the latter placing thesource of radiation directly into the tumor as implanted “seeds”. Thesenewer treatment modalities deliver greater doses of radiation to thetumor, which accounts for their increased effectiveness when compared tostandard external beam radiation therapy. Ionizing radiation withbeta-emitting radionuclides is considered the most useful forradiotherapeutic applications because of the moderate linear energytransfer (LET) of the ionizing particle (electron) and its intermediaterange (typically several millimeters in tissue). Gamma rays deliverdosage at lower levels over much greater distances. Alpha particlesrepresent the other extreme: they deliver very high LET dosage, but havean extremely limited range and must, therefore, be in intimate contactwith the cells of the tissue to be treated. In addition, alpha emittersare generally heavy metals, which limits the possible chemistry andpresents undue hazards from leakage of radionuclide from the area to betreated. Depending on the tumor to be treated all kinds of emitters areconceivable within the scope of the present disclosure. Furthermore, thepresent disclosure encompasses types of non-ionizing radiation like e.g.ultraviolet (UV) radiation, high energy visible light, microwaveradiation (hyperthermia therapy), infrared (IR) radiation and lasers. Ina particular embodiment of the present disclosure UV radiation isapplied.

Pharmaceutical Compositions

The present disclosure also includes pharmaceutical compositions ormedicaments containing the compounds of the present disclosure and apharmaceutically acceptable carrier, as well as methods of using thecompounds of the present disclosure to prepare such compositions andmedicaments. Typically, the compounds of formula IA or IB used in themethods of the present disclosure are formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, and itcan range from about 3 to about 8. Formulation in an acetate buffer atpH 5 is a suitable embodiment. In an embodiment, the inhibitory compoundfor use herein is sterile. The compound ordinarily will be stored as asolid composition, although lyophilized formulations or aqueoussolutions are acceptable.

In another embodiment, pharmaceutical compositions of the presentdisclosure may comprise a compound of formula IA or IB or apharmaceutically acceptable salt thereof, and one or more polymer(s) aspart of a solid dispersion (e.g., an amorphous solid dispersion). In anembodiment, the solid dispersion further comprises one or moresurfactants. In an embodiment, the pharmaceutical composition comprisinga compound of the present disclosure is a solid spray-dried dispersion.Pharmaceutical compositions comprising solid dispersions of a compoundof the present disclosure in a matrix may provide improved chemical andphysical properties and can be prepared by forming a homogeneoussolution or melt of the compound of the present disclosure and matrixmaterial followed by solidifying the mixture by cooling, or removal ofthe solvent. Such solid dispersions may show enhanced bioavailabilitywhen administered orally relative to oral compositions comprising theundispersed compound. A dispersion refers to a disperse system in whichone substance, the dispersed phase, is distributed, in discrete units,throughout a second substance (the continuous phase or vehicle). Thesize of the dispersed phase can vary considerably (e.g., colloidalparticles of nanometer dimension, to multiple microns in size). Ingeneral, the dispersed phases can be solids, liquids, or gases. In thecase of a solid dispersion, the dispersed and continuous phases are bothsolids. In pharmaceutical applications, a solid dispersion can include acrystalline therapeutically active compound (dispersed phase) in anamorphous polymer(s) (continuous phase), or alternatively, an amorphoustherapeutically active compound (dispersed phase) in an amorphouspolymer (continuous phase). An amorphous solid dispersion generallyrefers to a solid dispersion of two or more components, such as acompound of the present disclosure and polymer (or plurality ofpolymers), but possibly containing other components such as surfactantsor other pharmaceutical excipients, where the compound of the presentdisclosure is in the amorphous phase. In some embodiments, an amorphoussolid dispersion includes the polymer(s) (and optionally a surfactant)constituting the dispersed phase, and the compound of the presentdisclosure constitutes the continuous phase. In some embodiments, anamorphous solid dispersion includes the polymer(s) (and optionally asurfactant) constituting the continuous phase, and the compound of thepresent disclosure constitutes the dispersed phase.

An exemplary solid dispersion is a co-precipitate or a co-melt of acompound of the present disclosure with one or more polymer(s). A“co-precipitate” is produced after dissolving a compound of the presentdisclosure and one or more polymers in a solvent or solvent mixturefollowed by the removal of the solvent or solvent mixture. Sometimes theone or more polymers can be suspended in the solvent or solvent mixture.The solvent or solvent mixture includes organic solvents andsupercritical fluids. The solvent or solvent mixture can also contain anon-volatile solvent. A “co-melt” is produced after heating a compoundof the present disclosure and one or more polymers to melt, optionallyin the presence of a solvent or solvent mixture, followed by mixing,removal of at least a portion of the solvent if applicable, and coolingto room temperature at a selected rate. In some cases, solid dispersionsare prepared by adding a solution of a therapeutically active compoundand solid polymers followed by mixing and removal of the solvent orsolvent mixture. To remove the solvent or solvent mixture, vacuumdrying, spray drying, tray drying, lyophilization, and other dryingprocedures may be applied. Applying any of these methods usingappropriate processing parameters, according to this disclosure, wouldprovide the particular therapeutically active compound in an amorphousstate in the final solid dispersion product.

The composition of the present disclosure will be formulated, dosed, andadministered in a fashion consistent with good medical practice. Factorsfor consideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governedby such considerations, and is the minimum amount necessary to inhibitMAT2A activity. Such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole. Generally, the initialpharmaceutically effective amount of the compound of the presentdisclosure administered parenterally per dose will be in the range ofabout 0.01-2000 mg/kg, for example about 0.01 to about 200 mg/kg, about0.1 to 20 mg/kg of patient body weight per day, with the typical initialrange of compound used being 0.3 to 15 mg/kg/day. Oral unit dosageforms, such as tablets and capsules, may contain from about 25 to about200 mg of the compound of the present disclosure.

The compound of the present disclosure may be administered by anysuitable means, including oral, topical, transdermal, parenteral,subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, ifdesired for local treatment, intralesional administration. Parenteralinfusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration. An example of asuitable oral dosage form is a tablet containing about 1 mg, 2 mg, 5 mg,10 gm, 15 mg 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1250mg, 1500 mg, 1750 mg or 2000 mg of the compound of the presentdisclosure.

EXAMPLES

The present disclosure will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the present disclosure. Reagents and solvents were obtainedfrom commercial sources and used as received.

Abbreviations and terms list:

-   -   anhy. anhydrous    -   aq. aqueous    -   min minute(s)    -   mL milliliter    -   mmol millimole(s)    -   mol mole(s)    -   MS mass spectrometry    -   NMR nuclear magnetic resonance    -   TLC thin layer chromatography    -   HPLC high-performance liquid chromatography    -   RT(r.t.) room temperature

—Spectrum

-   -   Spectrum:    -   Hz hertz    -   δ chemical shift    -   J coupling constant    -   s singlet    -   d doublet    -   t triplet    -   q quartet    -   m multiplet    -   br broad    -   qd quartet of doublets    -   dquin doublet of quintets    -   dd doublet of doublets    -   dt doublet of triplets

Solvents and Reagents:

-   -   CHCl₃ chloroform    -   DCM dichloromethane    -   DMF dimethylformamide    -   Et₂O diethyl ether    -   EtOH ethyl alcohol    -   EtOAc ethyl acetate    -   EA ethyl acetate    -   MeOH methyl alcohol    -   MeCN acetonitrile    -   PE petroleum ether    -   THF tetrahydrofuran    -   AcOH acetic acid    -   HCl hydrochloric acid    -   H₂SO₄ sulfuric acid    -   NH₄Cl ammonium chloride    -   KOH potassium hydroxide    -   NaOH sodium hydroxide    -   K₂CO₃ potassium carbonate    -   Na₂CO₃ sodium carbonate    -   TFA trifluoroacetic acid    -   Na₂SO₄ sodium sulfate    -   NaBH₄ sodium borohydride    -   NaHCO₃ sodium bicarbonate    -   LiHMDS lithium hexamethyldisilylamide    -   NaHMDS sodium hexamethyldisilylamide    -   LAH lithium aluminum hydride    -   NaBH₄ sodium borohydride    -   LDA lithium diisopropylamide    -   Et₃N triethylamine    -   DMAP 4-(dimethylamino)pyridine    -   DIPEA N,N-diisopropylethylamine    -   NH₄OH ammonium hydroxide    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   HOBt 1-hydroxybenzotriazole    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    -   Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl    -   BINAP 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl

Example 1 Synthesis of Compounds

General Experimental Notes

In the following examples, the reagents (chemicals) were purchased fromcommercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and ShanghaiChemical Reagent Company), and used without further purification. Flashchromatography was performed on an Ez Purifier III using column withsilica gel particles of 200-300 mesh. Analytical and preparative thinlayer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thickness,Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR)spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland).Chemical shifts were reported in parts per million (ppm, δ) downfieldfrom tetramethylsilane. Mass spectra were given with electrosprayionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA).HPLC chromatographs were record on an Agilent 1200 Liquid Chromatography(Agilent, USA, column: Ultimate 4.6 mm×50 mm, 5 μm, mobile phase A: 0.1%formic acid in water; mobile phase B: acetonitrile). Microwave reactionswere run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).

Compound 101:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: Dimethyl 2-(4-methoxyphenyl)malonate

To dimethyl carbonate (3.2 L) was added slowly t-BuOK (500 g) at 0° C.and the mixture was stirred for 1 h at room temperature. Then methyl2-(4-methoxyphenyl)acetate (400 g) was added dropwise over 2 h andstirred at room temperature overnight. The reaction was quenched withwater (1.5 L), followed by extraction with EA (1 L*3). The combinedorganic layers were washed with brine (1 L), dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by flashchromatography eluting with PE/EA (20/1-5/1) to obtain the desiredproduct as white solid (400 g).

¹H NMR (CHLOROFORM-d): δ 7.33 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H),4.61 (s, 1H), 3.80 (s, 3H), 3.75 (s, 6H).

Step B:5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine 8 (470 g, 2 mol) anddimethyl-2-(4-methoxyphenyl)-malonate 2 (571 g, 2.4 mol, 1.2 eq.) inxylene (5 L) was refluxed for 18 h. The white precipitate was filteredoff and washed with DCM (5 L) to afford the title compound as whitesolid (610 g) which was used in the next step without furtherpurification.

¹H NMR (DMSO-d₆): δ 11.57 (br. s, 1H), 7.26-7.49 (m, 12H), 6.90-6.99 (m,2H), 3.78 (s, 3H). LC-MS: m/z 410.2 (M+H)⁺.

Step C:5,7-dichloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine

The6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dioxane(300 g, 0.73 mol) and phosphorus oxychloride (1200 mL, 12.90 mol) wereadded into a 2 L bottle. The reaction mixture was stirred at 100° C. for16 h. TLC indicated that the reaction was complete. The solvent andvolatile were removed in vacuo and the residue was dissolved in DCM (500mL). The mixture was added dropwise into the MeOH (2500 mL) at 0° C. Ayellow suspension formed during the course of addition. The mixture wasstirred at RT for 2 h and the precipitate was collected by filtrationand dried in vacuo to give desired product as yellow solid (290 g) whichwas used in the next step without further purification. LC-MS: m/z446.1, 448.1 (M+H)⁺.

Step D:5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine

The5,7-dichloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine 4(1.78 kg, 4 mol) and DCM (20 L) were added into the 30 L reactor. Themixture was cooled to −10° C. The sodium methoxide (1.48 L, 8 mol, 30%in MeOH) was dropwise such that the internal temperature is maintainedbelow 0° C. The reaction mixture was stirred at RT for 2 h. TLCindicated that the reaction was completed. The ice water (10 L) wasadded and the reaction mixture was stirred at RT for 1 h. The organiclayer was collected and the aqueous layer was extracted with DCM (5L*1). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated. The residue was dissolved in DCM (15 L) and the MeOH (60L) was added. The turbid liquid was stirred at RT for 3 h and theprecipitate was collected by filtration and dried in vacuo to give thetitle Intermediate 5 as a yellow solid (1.35 kg).

¹H NMR (CHLOROFORM-d): δ 7.66-7.73 (m, 2H), 7.53-7.61 (m, 2H), 7.30-7.46(m, 8H), 7.00-7.09 (m, 2H), 4.16 (s, 3H), 3.92 (s, 3H). LC-MS: m/z 442.1(M+H)⁺.

Step E:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of Intermediate5,5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine,(600 mg, 1.36 mmol), 3-aminopyridazine (258 mg, 2.72 mmol, 2 eq.),Pd(OAc)₂ (61 mg, 0.27 mmol, 0.2 eq.), Xantphos (197 mg, 0.34 mmol, 0.25eq.) and Cs₂CO₃ (890 mg, 2.72 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) wasstirred at 120° C. through microwave irradiation for 1 hour under N₂atmosphere. The mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyto afford the desired product 6 as a yellow solid. LC-MS: m/z 501.0(M+H)⁺.

Step F:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of Intermediate 6 (360 mg, 0.72 mmol) in 4M HCl in1.4-dioxane (5 mL) was stirred at r.t. for 2 hours. Solvent and volatilewere removed in vacuo. The residue was dissolved in DCM (5 mL) andtreated with aq saturated NaHCO₃. The organic phase was separated andwashed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuoto afford the desired product 7.

¹H NMR (DMSO-d₆): δ 15.25 (br. s., 1H), 9.21 (br. s., 1H), 8.86 (br. s.,1H), 7.63 (br. s., 2H), 7.44-7.58 (m, 4H), 7.28-7.44 (m, 8H), 7.05 (d,J=8.6 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 486.9 (M+H)⁺.

The following compounds were prepared according to the procedure forcompound 101, step E and F, starting from intermediate 5 therein. Step Ewas performed using appropriate amine 9, base (Cs₂CO₃, K₂CO₃, Na₂CO₃,and etc.) and catalyst/ligand under microwave or thermal heating, in1,4-dioxane unless otherwise noted. Step F was performed using 5 mL of4M HCl in dioxane unless otherwise noted. Purifications were performedusing the methods used in Example 101, unless otherwise noted.

Compound 102:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol),pyridin-2-amine (213 mg, 2.26 mmol), Pd(OAc)₂ (50 mg, 0.23 mmol),xantphos (165 mg, 0.28 mmol), and Na₂CO₃ (240 mg, 2.26 mmol) in1,4-dioxane (10 mL) under heating at 100° C. for 4 h under N₂. LC-MS:m/z 500.0 (M+H)⁺.

Step F:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(300 mg, 0.6 mmol) was dissolved in HCl/1,4-dioxane (5 mL). The solutionwas stirred at r.t. overnight. The precipitate was filtered off andwashed with CH₂Cl₂ (3*1 mL) to give a yellow solid. The solid was thendissolved in CH₂Cl₂/MeOH (10/1, 3 mL). After 3 mL of NH₃-MeOH was added,the solution was stirred at r.t. overnight to give the title compound.

¹H NMR (TRIFLUOROACETIC ACID-d): δ 8.05-8.15 (m, 1H), 7.79 (d, J=5.6 Hz,1H), 7.59 (d, J=7.2 Hz, 2H), 7.46-7.56 (m, 6H), 7.36-7.46 (m, 4H),7.25-7.34 (m, 2H), 7.16 (d, J=8.8 Hz, 2H), 3.97 (s, 3H). LC-MS: m/z486.2 (M+H)⁺.

Compound 103:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol),pyridin-3-amine (117 mg, 1.24 mmol), Pd(OAc)₂ (25 mg, 0.113 mmol),xantphos (131 mg, 0.226 mmol), Cs₂CO₃ (737 mg, 2.26 mmol) in dioxane (20mL) under heating to 110° C. for 4 h under N₂. LC-MS: m/z 500.2 (M+H)⁺.

Step F: To a solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(150 mg, 0.309 mmol) in MeOH (10 mL) was added 4N HCl solution indioxane (10 mL). The reaction mixture was heated to 50° C. for 2 h. Themixture was concentrated in vacuo. The residue was suspended insaturated NaHCO₃ solution to give the desired product6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 8.48 (br. s., 1H), 8.30 (br. s., 1H), 8.10 (d, J=4.6Hz, 1H), 7.71 (br. s., 1H), 7.46 (br. s., 3H), 7.14-7.41 (m, 11H), 6.93(d, J=8.1 Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 486.2 (M+H)⁺.

Compound 104:6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)nicotinonitrile

Step E stoichiometry: Intermediate 5 (300 mg, 0.68 mmol),6-aminonicotinonitrile (161.7 mg, 1.36 mmol), palladium diacetate (30.5mg, 0.14 mmol), Xantphos (117.8 mg, 0.20 mmol) and Cesium carbonate(553.0 mg, 1.70 mmol) in 1,4-dioxane (10 mL) under heating to 110° C.for 12 hours under nitrogen atmosphere. LC-MS: m/z 525.2 (M+H)⁺.

Step F: The solution of6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)nicotinonitrile(40 mg, 0.07 mmol) in HCl solution (1.0 M in 1,4-dioxane, 6 mL) wasstirred at room temperature for 12 hours. The mixture was concentrated,and NH₄OH (5 mL) was added thereto to obtain6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)nicotinonitrile.

¹H NMR (DMSO-d₆): δ 14.21 (br. s., 1H), 9.53 (s, 1H), 8.53 (d, J=2.1 Hz,1H), 8.11 (dd, J=8.9, 2.1 Hz, 1H), 7.50-7.62 (m, 4H), 7.36-7.45 (m, 6H),7.29-7.36 (m, 3H), 7.03 (d, J=8.6 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z511.3 (M+H)⁺.

Compound 105:5-((5-fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol),5-fluoropyridin-2-amine (112 mg, 1.0 mmol), Pd(OAc)₂ (56 mg, 0.25 mmol),xantphos (173 mg, 0.3 mmol), Cs₂CO₃ (117 mg, 1.1 mmol) in dioxane (20mL) under heating to 100° C. for 4 h under N₂. LC-MS: m/z 518.2 (M+H)+.

Step F: To a solution ofN-(5-fluoropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.10 mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane(10 mL). The reaction mixture was heated to 50° C. for 2 h. The mixturewas concentrated in vacuo. The residue was suspended in saturated NaHCO₃solution to give the desired product5-((5-fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 14.87 (br. s., 1H), 9.08 (s, 1H), 7.94-8.07 (m, 1H),7.71-7.88 (m, 1H), 7.50-7.64 (m, 4H), 7.38-7.44 (m, 6H), 7.29-7.35 (m,J=8.5 Hz, 2H), 6.99-7.10 (m, J=8.5 Hz, 2H), 3.83 (s, 3H). LC-MS: m/z503.9 (M+H)⁺.

Compound 106:5-((5-chloropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol),5-chloropyridin-2-amine (135 mg, 0.9 mmol), Pd(OAc)₂ (51 mg, 0.23 mmol),xantphos (156 mg, 0.27 mmol), and Na₂CO₃ (105 mg, 0.9 mmol) in1,4-dioxane (5 mL) under heating at 100° C. for 16 h under N₂. LC-MS:m/z 533.9, 535.9 (M+H)⁺.

Step F:N-(5-chloropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(80 mg, 0.15 mmol) was dissolved in HCl-1,4-dioxane (5 mL). The solutionwas stirred at r.t. overnight. The precipitate was filtered off andwashed with CH₂Cl₂ (3 mL) to give a yellow solid. The solid was thendissolved in CH₂Cl₂/MeOH (10/1, 2 mL). After 1 mL of NH₃-MeOH was added,the solution was stirred at r.t. overnight to give the title compound 7.

¹H NMR (DMSO-d₆): δ 14.72 (s, 1H), 9.16 (s, 1H), 8.01 (s, 1H), 7.88 (d,J=9.2 Hz, 1H), 7.49-7.66 (m, 4H), 7.40 (d, J=7.2 Hz, 9H), 7.32 (d, J=8.2Hz, 2H), 7.04 (d, J=8.2 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 519.9, 521.9(M+H)⁺.

Compound 107:6-(4-methoxyphenyl)-5-((5-nitropyridin-2-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) and5-nitropyridin-2-amine (472 mg, 3.39 mmol, 3 eq) and Pd(OAc)₂ (51 mg,0.23 mmol, 0.2 eq), Xantphos (262 mg, 0.45 mmol, 0.4 eq) and Na₂CO₃ (360mg, 3.394 mmol, 3 eq) in 1.4-dioxane (10 mL) was stirred and warmed upto 100° C. under microwave irradiation for 1 hours under N₂ atmosphere.

¹H NMR (DMSO-d₆) δ 9.03 (d, J=2.7 Hz, 1H), 8.55-8.66 (m, 2H), 8.12 (s,1H), 7.58-7.65 (m, 2H), 7.43-7.54 (m, 9H), 7.31-7.36 (m, 1H), 7.19 (d,J=8.5 Hz, 2H), 4.16 (s, 3H), 3.87 (s, 3H). LC-MS: m/z 545.2 (M+H)⁺.

Step F: A solution of7-methoxy-6-(4-methoxyphenyl)-N-(5-nitropyridin-2-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.092 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at roomtemperature for 3 hours. The reaction mixture was concentrate in vacuo,The residue was dissolved in 7N amine in methanol and stirred at roomtemperature for 2 h. The mixture was concentrated in vacuo to give6-(4-methoxyphenyl)-5-((5-nitropyridin-2-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 13.95 (br. s., 1H), 9.82-9.91 (m, 1H), 8.85 (br. s.,1H), 8.45 (br. s., 1H), 7.54 (dd, J=6.18, 2.96 Hz, 4H), 7.37-7.45 (m,5H), 7.33 (m, J=8.86 Hz, 2H), 7.02 (m, J=8.60 Hz, 2H), 3.81 (s, 3H).LC-MS: m/z 531.0 (M+H)⁺.

Compound 108:5-(5-hydroxypyridin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (160 mg, 0.362 mmol),5-(tert-butyldimethylsilyloxy) pyridin-2-amine (162 mg, 0.724 mmol),palladium(II) acetate (16 mg, 0.0724 mmol), xantphos (84 mg, 0.145 mmol)and sodium carbonate (77 mg, 0.724 mmol) in 1.4-dioxane (10 mL) underheating to reflux for 4 hours under nitrogen atmosphere. LC-MS: m/z630.3 (M+H)⁺.

Step F: A mixture ofN-(5-(tert-butyldimethyl-silyloxy)pyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(80 mg, 0.127 mmol) and HCl solution (4N in dioxane, 10 mL) was stirredat room temperature for 6 h. Then conc. HCl (0.5 mL) was added into themixture. The resulting mixture was stirred at the same temperature for 4h. The mixture was quenched with ammonia solution (7N in methanol) to pH7 to afford5-(5-hydroxypyridin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneas a white solid.

¹H NMR (TFA-d): δ 7.71-7.80 (m, 1H), 7.57 (d, J=7.32 Hz, 2H), 7.44-7.54(m, 7H) 7.30-7.43 (m, 4H), 7.18 (d, J=9.46 Hz, 1H), 7.13 (d, J=8.54 Hz,2H), 3.94 (s, 3H). LC-MS: m/z 502.4 (M+H)⁺.

Compound 109:5-((4-hydroxypyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (80 mg, 0.18 mmol) and2-aminopyridin-4-ol (30 mg, 0.27 mmol, 1.5 eq) and Pd(OAc)₂ (6.1 mg,0.03 mmol, 0.15 eq), Xantphos (15.7 mg, 0.03 mmol, 0.15 eq) and Cs₂CO₃(120 mg, 0.36 mmol, 2.0 eq) in 1.4-dioxane (3 mL) at 110° C. for 1 hunder microwave radiation under N₂ atmosphere. LC-MS: m/z 516.0 (M+H)⁺.

Step F: A solution of2-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyridin-4-ol(40 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30°C. for 2 hours to obtain the title compound.

¹H NMR (CHLOROFORM-d): δ 7.66 (s, 1H), 7.57 (d, J=7.2 Hz, 2H), 7.54-7.44(m, 6H), 7.44-7.34 (m, 4H), 7.11 (s, 2H), 6.72 (m, 2H), 3.99 (s, 1H),3.94 (s, 3H). LC-MS: m/z 502.0 (M+H)⁺.

Compound 110:5-((6-fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol),6-fluoropyridin-2-amine (101 mg, 0.9 mmol), Pd(OAc)₂ (20 mg, 0.09 mmol),xantphos (65 mg, 0.11 mmol), and Cs₂CO₃ (293 mg, 0.9 mmol) in1,4-dioxane (5 mL) under heating at 100° C. for 16 h under N₂. LC-MS:m/z 518.1 (M+H)⁺.

Step F:N-(6-fluoropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(120 mg, 0.23 mmol) was dissolved in HCl-1,4-dioxane (5 mL). Thesolution was stirred at r.t. overnight. The precipitate was filtered offand washed with CH₂Cl₂ (3 mL) to give a yellow solid. The solid was thendissolved in CH₂Cl₂/MeOH (10/1, 2 mL). After 1 mL of NH₃-MeOH was added,the solution was stirred at r.t. overnight to give the title compound 7.

¹H NMR (DMSO-d₆): δ 13.33 (s, 1H), 9.16 (s, 1H), 7.86 (q, J=8.4 Hz, 1H),7.54-7.48 (m, 2H), 7.34-7.48 (m, 8H), 7.32 (d, J=8.6 Hz, 2H), 7.09 (d,J=8.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 3.81 (s,3H). LC-MS: m/z 503.9 (M+H)⁺.

Compound 111:6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinonitrile

Compound 1126-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinamide

Step E stoichiometry: Intermediate 5 (800 mg, 1.8 mmol) and6-aminopicolinonitrile (281 mg, 2.36 mmol, 1.3 eq) and Pd(OAc)₂ (61.2mg, 0.27 mmol, 0.15 eq), Xantphos (157.4 mg, 0.27 mmol, 0.15 eq) andCs₂CO₃ (1.2 g, 3.63 mmol, 2.0 eq) in 1.4-dioxane (15 mL) at 110° C. for1 h under microwave irradiation under N₂ atmosphere. LC-MS: m/z 524.9(M+H)⁺.

Step F: A solution of6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinonitrile(220 mg, 0.42 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30°C. for 5 hours to obtain the title compounds6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinonitrileand6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinamide.

6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinonitrile

¹H NMR (DMSO-d₆) δ: 12.69 (s, 1H), 9.31 (s, 1H), 7.87 (dd, J=8.8, 7.6Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.54-7.45 (m, 4H), 7.44-7.34 (m, 7H),7.32 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z510.9 (M+H)⁺.

6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinamide

¹H NMR (DMSO-d₆) δ: 12.42 (s, 1H), 9.00 (s, 1H), 7.97 (s, 1H), 7.79 (t,J=8.0 Hz, 1H), 7.55-7.43 (m, 4H), 7.37 (m, 10H), 7.19 (d, J=8.4 Hz, 1H),7.00 (d, J=8.4 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 529.0 (M+H)⁺.

Compound 113:5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy-phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (200 mg, 0.452 mmol),3-(tert-butyl-dimethylsilyloxy)pyridin-2-amine (202 mg, 0.904 mmol),palladium(II) acetate (31 mg, 0.136 mmol), xantphos (157 mg, 0.272 mmol)and sodium carbonate (96 mg, 0.904 mmol) in 1.4-dioxane (10 mL) wasstirred and heated to reflux for 4 hours under nitrogen atmosphere. Thereaction was then cooled to room temperature and filtered. The filtratewas concentrated in vacuum to afford5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy-phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (TFA-d): δ 8.33 (d, J=8.33 Hz, 1H), 7.99 (d, J=5.10 Hz, 1H),7.56-7.71 (m, 8H), 7.48-7.54 (m, 4H), 7.42 (dd, J=8.33, 5.91 Hz, 1H),7.34 (d, J=8.60 Hz, 2H), 4.10 (s, 3H). LC-MS: m/z 502.4 (M+H)⁺.

Compound 114:2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)isonicotinonitrile

Step E stoichiometry: Intermediate 5 (200 mg, 0.452 mmol) and2-aminoisonicotinonitrile (108 mg, 0.9 mmol) and Pd(OAc)₂ (102 mg, 0.434mmol), Xantphos (315 mg, 0.54 mmol) and Cs₂CO₃ (327 mg, 1.0 mmol) in1.4-dioxane (10 mL) under heating to 110° C. for 1 hour throughmicrowave irradiation under N₂ atmosphere. LC-MS: m/z 525.2 (M+H)⁺.

Step F: A mixture of2-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-ylamino)isonicotinonitrile (15 mg, 0.03 mmol) in HCl solution (4 M in dioxane, 1mL) was stirred at room temperature overnight. The mixture was quenchedwith NH₃ solution (7M in methanol) to pH 7-8 to afford6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 8.25 (d, J=5.37 Hz, 1H), 7.77 (s, 1H), 7.49-7.63 (m,4H), 7.37-7.47 (m, 7H), 7.34 (m, J=8.60 Hz, 2H), 7.06 (m, J=8.60 Hz,2H), 3.84 (s, 3H). LC-MS: m/z 511.2 (M+H)⁺.

Compound 115:2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrimidine-5-carbonitrile

A mixture of Intermediate 5 (200 mg, 0.452 mmol) and2-aminopyrimidine-5-carbonitrile (108 mg, 0.904 mmol) and Pd(OAc)₂ (31mg, 0.136 mmol), Xantphos (157 mg, 0.272 mmol) and Na₂CO₃ (96 g, 0.904mmol) in 1.4-dioxane (10 mL) was stirred and heated to reflux for 4hours under N₂ atmosphere. The reaction was then cooled to roomtemperature and filtered. The filtrate was concentrated in vacuum toafford2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrimidine-5-carbonitrile.

¹H NMR (DMSO-d₆): δ 12.77 (bs, 1H), 10.27 (bs, 1H), 8.88 (s, 2H),7.43-7.52 (m, 4H), 7.35-7.40 (m, 4H), 7.32 (d, J=7.63 Hz, 2H), 7.25 (d,J=8.54 Hz, 2H), 6.93 (d, J=8.24 Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 512.2(M+H)⁺.

Compound 116:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (440 mg, 1 mmol), pyrimidin-4-amine(190 mg, 2 mmol, 2 eq.), Pd(OAc)₂ (22 mg, 0.1 mmol, 0.1 eq.), Xantphos(116 mg, 0.2 mmol, 0.2 eq.) and Cs₂CO₃ (390 mg, 1.2 mmol, 1.2 eq.) in1.4-dioxane (10 mL) under heating at 100° C. through microwaveirradiation for 1 hour under N₂ atmosphere. LC-MS: m/z 501.5 (M+H)⁺.

Step F: A solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(260 mg, 0.52 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t.for 16 hours to give the title compound.

¹H NMR (DMSO-d₆): δ 13.13 (s, 1H), 11.25 (s, 1H), 8.90 (s, 1H), 8.45 (d,J=7.0 Hz, 1H), 7.44-7.53 (m, 4H), 7.25-7.42 (m, 7H), 7.18 (d, J=6.4 Hz,1H), 6.95 (d, J=8.8 Hz, 2H), 3.77 (s, 3H). LC-MS: m/z 487.0 (M+H)⁺.

Compound 117:5-((6-aminopyrimidin-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (237 mg, 0.538 mmol),pyrimidine-4,6-diamine (118.2 mg, 1.07 mmol, 2 eq.), Pd(OAc)₂ (60 mg,0.269 mmol, 0.5 eq.), Xantphos (186.5 mg, 0.322 mmol, 0.6 eq.) andNa₂CO₃ (125 mg, 1.184 mmol, 2.2 eq.) in 1.4-dioxane (5 mL) under heatingat 100° C. for 3 hour under N₂ atmosphere. LC-MS: m/z 516.5 (M+H)⁺.

Step F: A solution ofN4-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-4,6-diamine(90 mg, 0.17 mmol) in 4M HCl in 1.4-dioxane (3 mL) was stirred at r.t.for 3 hours to give the title compound.

¹H NMR (DMSO-d₆): δ 13.54 (br. s., 1H), 9.94 (br. s., 1H), 8.27 (s, 1H),7.82 (br. s., 2H), 7.43-7.52 (m, 4H), 7.31-7.42 (m, 6H), 7.28 (d, J=8.6Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 6.02 (br. s., 1H), 3.78 (s, 3H). LC-MS:m/z 502.9 (M+H)⁺.

Compound 118:6-(4-methoxyphenyl)-5-((2-methoxypyrimidin-4-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (300 mg, 0.67 mmol),2-methoxypyrimidin-4-amine (169 mg, 1.25 mmol), Pd(OAc)₂ (48 mg, 0.067mmol), xantphos (72 mg, 0.13 mmol), Cs₂CO₃ (409 mg, 1.25 mmol) indioxane (20 mL) under heating to 110° C. for 4 h under N₂. LC-MS: m/z531.2 (M+H)⁺.

Step F: To a solution of7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxypyrimidin-4-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(100 mg, 0.19 mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane(10 mL). The reaction mixture was heated to 50° C. for 2 h. The mixturewas concentrated in vacuo. The residue was suspended in saturated NaHCO₃solution to give the desired product6-(4-methoxyphenyl)-5-((2-methoxypyrimidin-4-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (TFA): δ 8.30 (d, J=7.0 Hz, 1H), 7.63-7.78 (m, 3H), 7.40-7.63 (m,8H), 7.27 (d, J=7.5 Hz, 2H), 7.04 (d, J=7.0 Hz, 1H), 3.98 (s, 3H), 3.48(s, 3H). LC-MS: m/z 517.0 (M+H)⁺.

Compound 119:5-(2-hydroxypyrimidin-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenyl-pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxypyrimidin-4-yl)-2,3-diphenyl-pyrazolo[1,5-a]pyrimidin-5-amine(126 mg, 0.244 mmol) and conc.HCl (10 mL) was heated to reflux for 2days. The mixture was quenched with ammonia solution (7N in methanol) topH 7 and concentrated to afford5-(2-hydroxypyrimidin-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenyl-pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 7.52 (d, J=6.71 Hz, 3H), 7.45 (d, J=6.71 Hz, 2H),7.20-7.40 (m, 9H), 7.05-7.19 (m, 2H), 6.99 (bs, 2H), 3.80 (s, 3H).LC-MS: m/z 503.2 (M+H)⁺.

Compound 120:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (500 mg, 1.13 mmol) and pyrimidin-5-amine(323 mg, 3.39 mmol, 3 eq) and Pd(OAc)₂ (51 mg, 0.23 mmol, 0.2 eq),Xantphos (262 mg, 0.45 mmol, 0.4 eq) and Na₂CO₃ (356 mg, 3.39 mmol, 3eq) in 1.4-dioxane (10 mL) was stirred and warmed up to 100° C. withmicrowave irradiation for 1 hours under N₂ atmosphere. The reaction wasthen cooled to r.t. to obtain6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 8.65 (s, 2H), 8.52 (br. s., 1H), 7.54 (d, J=8.87 Hz,1H), 7.34-7.49 (m, 8H), 7.31 (br. s., 3H), 6.93 (br. s., 1H), 3.68-3.84(m, 3H). LC-MS: m/z 487.0 (M+H)⁺.

Compound 121:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.4535 mmol),pyrimidin-2-amine (86 mg, 0.91 mmol, 2 eq.), Pd(OAc)₂ (102 mg, 0.4535mmol, 1 eq.), Xantphos (314.5 mg, 0.54 mmol, 1.2 eq.) and Cs₂CO₃ (327mg, 1 mmol, 2.2 eq.) in 1.4-dioxane (4 mL) under heating at 110° C. for1 hour through microwave irradiation under N₂ atmosphere. LC-MS: m/z501.6 (M+H)⁺.

Step F: A solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(60 mg, 0.12 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t.for 2 hours. Solvent and volatile were removed in vacuo. The residue wasdissolved in DCM (5 mL) and treated with saturated NaHCO₃. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 14.08 (br. s., 1H), 8.60 (s, 1H), 8.57 (d, J=4.84Hz, 2H), 7.52-7.62 (m, 4H), 7.40-7.49 (m, 6H), 7.37 (d, J=8.60 Hz, 2H),7.18 (t, J=4.97 Hz, 1H), 7.08 (d, J=8.60 Hz, 2H), 3.84 (s, 3H). LC-MS:m/z 487.2 (M+H)⁺.

Compound 122:5-((5-chloropyrimidin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol),5-chloropyrimidin-2-amine (129 mg, 1.0 mmol), palladium diacetate (56mg, 0.2 mmol), Xantphos (173 mg, 0.3 mmol) and sodium carbonate (117 mg,1.1 mmol) in 1,4-dioxane (20 mL) under refluxing for 4 hours undernitrogen atmosphere. LC-MS: m/z 535.1 (M+H)⁺.

Step F: The solution ofN-(5-chloropyrimidin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.1 mmol) in HCl solution (4.0 M in 1,4-dioxane, 5 mL) wasstirred at room temperature for 2 hours. The mixture was concentrated,and NH₄OH (8 mL) was added thereto to obtain6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)nicotinonitrile.

¹H NMR (DMSO-d₆): δ 13.13 (s, 1H), 9.27 (s, 1H), 8.60 (s, 2H), 7.29-7.55(m, 12H), 7.00 (d, J=8.4 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 520.9 (M+H)⁺.

Compound 123:5-((6-aminopyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (132 mg, 0.3 mmol) andN-(6-aminopyridazin-3-yl)acetamide (93 mg, 0.2 mmol, 2 eq) and Pd(OAc)₂(10 mg, 0.04 mmol, 0.4 eq), Xantphos (24 mg, 0.04 mmol, 0.4 eq) andCs₂CO₃ (65 mg, 0.2 mmol, 2 eq) in 1.4-dioxane (5 mL) under heating at120° C. through microwave irradiation for 1 hours under N₂ atmosphere.LC-MS: m/z 558.2 (M+H)⁺.

Step F: A mixture ofN-(6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyridazin-3-yl)acetamide(55.7 mg, 0.1 mmol) and potassium tert-butoxide in 1.4-dioxane (5 mL)was stirred at 100° C. for 16 hours. The mixture was filtered andconcentrated in vacuo to give5-((6-aminopyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 7.50 (br. s., 2H), 7.40 (br. s., 3H), 7.33 (d,J=8.86 Hz, 8H), 7.04 (d, J=8.06 Hz, 3H), 6.89 (br. s., 1H), 3.82 (s,4H). LC-MS: m/z 502.1 (M+H)⁺.

Compound 124:6-(4-methoxyphenyl)-5-((6-methoxypyridazin-3-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.453 mmol) and6-methoxypyridazin-3-amine (169.8 mg, 1.358 mmol, 3 eq), Pd(OAc)₂ (20.3mg, 0.091 mmol, 0.2 eq), Xant-phos (104.7 mg, 0.181 mmol, 0.4 eq) andNa₂CO₃ (143.9 mg, 1.358 mmol, 3 eq) in 1.4-dioxane (5 mL) under heatingat 100° C. through microwave irradiation for 1 hour under N₂ atmosphere.LC-MS: m/z 531.2 (M+H)⁺.

Step F: A solution of7-methoxy-6-(4-methoxyphenyl)-N-(6-methoxypyridazin-3-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.094 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated in vacuoto give the title compound.

¹H NMR (CHLOROFORM-d): δ 7.74 (d, J=9.46 Hz, 1H), 7.59 (d, J=9.46 Hz,1H), 7.22-7.48 (m, 12H), 7.07 (d, J=6.41 Hz, 2H), 4.07 (s, 3H), 3.88 (s,3H). LC-MS: m/z 517.0 (M+H)⁺.

Compound 125:5-((6-chloropyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol),6-chloropyridazin-3-amine (101 mg, 0.9 mmol, 2 eq.), and Pd(OAc)₂ (20mg, 0.09 mmol, 0.2 eq.), Xantphos (65 mg, 0.11 mmol, 0.3 eq.) and Cs₂CO₃(293 mg, 0.9 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) under heating at 120°C. through microwave irradiation for 1 hour under N₂ atmosphere. LC-MS:m/z 534.9, 536.9 (M+H)⁺.

Step F: The solution ofN-(6-chloropyridazin-3-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(60 mg, 0.12 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at r.t.overnight. Solvent and volatile were removed in vacuo. The residue wasdissolved in DCM (5 mL) and treated with saturated NaHCO₃. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆/TRIFLUOROACETIC ACID-d (v: 1/5)): δ 7.73 (d, J=9.4 Hz,1H), 7.65 (d, J=9.4 Hz, 1H), 7.42-7.54 (m, 4H), 7.31-7.40 (m, 8H), 7.01(d, J=8.6 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 520.9, 522.9 (M+H)⁺

Compound 126:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (100 mg, 0.230 mmol),pyrazin-2-amine (44 mg, 0.460 mmol), palladium(II) acetate (57 mg, 0.250mmol), xantphos (160 mg, 0.276 mmol) and cesium carbonate (165 mg, 0.506mmol) in 1,4-dioxane (10 mL) under heating at 100° C. through microwaveirradiation for 1 hour under nitrogen atmosphere. LC-MS: m/z 501.2(M+H)⁺.

Step F: A mixture of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.0996 mmol) in hydrogen chloride solution (4 M in dioxane, 3mL) was stirred at room temperature for 10 hours. The mixture wasevaporated to dryness. The residue was resolved in dichloromethanesolution (with 10% methanol) and basified with aqueous ammonia to pH 8to afford6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrazin-2-ylamino)-pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 14.27 (br. s., 1H), 9.93 (s, 1H), 9.38 (s, 1H), 8.61(s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.56 (m, 5H), 7.36 (d, J=8.60 Hz,5H), 7.06 (d, J=8.33 Hz, 3H), 3.83 (s, 3H). LC-MS: m/z 487.2 (M+H)⁺.

Compound 127:5-((3-hydroxypyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (150 mg, 0.34 mmol) and3-aminopyrazin-2-ol (49 mg, 0.44 mmol, 1.3 eq), Pd(OAc)₂ (11 mg, 0.05mmol, 0.15 eq), Xantphos (29 mg, 0.05 mmol, 0.15 eq) and Cs₂CO₃ (221 mg,0.68 mmol, 2.0 eq) in 1.4-dioxane (10 mL). under heating at 110° C.through microwave irradiation for 1 hour under nitrogen atmosphere.LC-MS: m/z 516.9 (M+H)⁺.

Step F: A solution of3-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrazin-2-ol(15 mg, 0.03 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30° C.for 5 hours. The reaction mixture was concentrated in vacuum to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 14.12 (br. s., 1H), 12.64 (br. s., 1H), 8.50 (s,1H), 7.51-7.65 (m, 4H), 7.33-7.47 (m, 8H), 7.02-7.17 (m, 3H), 6.78 (d,J=4.4 Hz, 1H), 3.85 (s, 3H). LC-MS: m/z 503.0 (M+H)⁺.

Compound 128:5-((3-aminopyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (500 mg, 1.13 mmol), pyrazine-2,3-diamine(249 mg, 2.26 mmol, 2 eq.), Pd(OAc)₂ (254 mg, 1.13 mmol, 1 eq.),Xantphos (653 mg, 1.13 mmol, 1 eq.) and Cs₂CO₃ (737 mg, 2.26 mmol, 2.0eq.) in 1.4-dioxane (15 mL) was stirred at 120° C. through microwaveirradiation for 1 hour under N₂ atmosphere. The mixture was filteredthrough celite, and the filtrate was concentrated in vacuo to afford thetitle compound.

¹H NMR (TRIFLUOROACETIC ACID-d): δ 7.49-7.64 (m, 6H), 7.36-7.49 (m, 7H),7.33 (d, J=4.0 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 3.91 (s, 3H). LC-MS: m/z502.1 (M+H)⁺.

Compound 129:5-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol),5-aminopyrazine-2-carbonitrile (163 mg, 1.36 mmol),tris(dibenzylideneacetone)dipalladium(0) (311 mg, 0.34 mmol), xantphos(216 mg, 0.374 mmol) and sodium carbonate (264 mg, 2.5 mmol) in1,4-dioxane (20 mL) under heating to reflux for 1 hour under N₂atmosphere. LC-MS: m/z 526.2 (M+H)⁺.

Step F: To a solution of5-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile(100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HCl solution (4Min dioxane, 10 mL). The reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was quenched with ammonia solution (7M inmethanol) to pH 7-8 to give5-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile.

¹H NMR (DMSO-d₆): δ 9.79 (s, 1H), 8.60 (s, 1H), 7.95 (s, 1H), 7.57 (d,J=6.45 Hz, 2H), 7.47 (d, J=7.25 Hz, 2H), 7.27-7.42 (m, 7H), 7.17 (d,J=6.72 Hz, 1H), 7.01 (d, J=8.33 Hz, 2H), 3.81 (s, 3H). LC-MS: m/z 512.2(M+H)⁺.

Compound 130:5-((5-aminopyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (440 mg, 1.0 mmol),pyrazine-2,5-diamine (293 mg, 2.0 mmol), palladium(II) acetate (112 mg,0.50 mmol), xantphos (347 mg, 0.6 mmol) and cesium carbonate (1.2 g, 4.0mmol) in 1,4-dioxane (20 mL) under heating at 110° C. for 1 hour throughmicrowave irradiation under N₂ atmosphere. LC-MS: m/z 516.2 (M+H)⁺.

Step F: A mixture ofN²-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)pyrazine-2,5-diamine (50 mg, 0.10 mmol) in hydrogen chloride solution (4M in dioxane, 5 mL) was stirred at room temperature for 16 hours. Themixture was evaporated to dryness. The residue was resolved indichloromethane solution (with 10% methanol), basified with aqueousammonia to pH 8 to afford5-(5-aminopyrazin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 14.30 (s, 1H), 8.77 (s, 1H), 8.07 (s, 1H), 7.54-7.51(m, 4H), 731-7.43 (m, 7H), 7.05 (d, J=8.4 Hz, 2H), 6.23 (s, 2H), 3.83(s, 1H). LC-MS: m/z 502.0 (M+H)⁺.

Compound 131:6-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol),6-aminopyrazine-2-carbonitrile (163 mg, 1.36 mmol), palladium(II)acetate (84 mg, 0.374 mmol), xantphos (215 mg, 0.374 mmol) and cesiumcarbonate (741 mg, 2.27 mmol) in 1,4-dioxane (10 mL) under heating at110° C. for 1 hour through microwave irradiation under N₂ atmosphere.LC-MS: m/z 526.2 (M+H)⁺.

Step F: To a solution of6-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL)was added HCl solution (4M in dioxane, 2 mL). The reaction mixture wasstirred at room temperature for 18 h. The mixture was evaporated todryness. The residue was resolved in dichloromethane solution (with 10%methanol) and washed with aqueous sodium bicarbonate to pH 8. Theorganic phase was dried over sodium afford6-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)-pyrazine-2-carbonitrile.

¹H NMR (DMSO-d₆): δ 8.57-8.71 (m, 2H) 7.44-7.65 (m, 4H) 7.21-7.42 (m,8H) 6.99 (d, J=8.55 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 512.2 (M+H)⁺.

Compound 132:5-((1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (800 mg, 1.81 mmol),1,3,5-triazin-2-amine (348 mg, 3.62 mmol), and Pd(OAc)₂ (81 mg, 0.36mmol), Xantphos (260 mg, 0.45 mmol) and Na₂CO₃ (384 mg, 3.62 mmol) in1.4-dioxane (15 mL) under heating at 120° C. for 4 hours under N₂atmosphere. LC-MS: m/z 502.0 (M+H)⁺.

Step F:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,3,5-triazin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(500 mg, 1.0 mmol) was dissolved in HCl-1,4-dioxane (10 mL). Thesolution was stirred at r.t. for 2 h. The precipitate was filtered offand washed with CH₂Cl₂ (3*1 mL) to give a yellow solid. The solid wasthen dissolved in CH₂Cl₂/MeOH (10/1, 3 mL). After 3 mL of NH₃-MeOH wasadded, the solution was stirred at r.t. overnight to give the titlecompound.

¹H NMR (DMSO-d₆): δ 12.71 (br. s, 1H), 10.24 (br. s., 1H), 8.70 (s, 2H),7.41-7.50 (m, 4H), 7.29-7.41 (m, 6H), 7.21-7.27 (m, 2H), 6.93 (d, J=8.6Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 488.0 (M+H)⁺.

Compound 133:5-((1,2,4-triazin-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol),1,2,4-triazin-5-amine (100 mg, 1.0 mmol), palladium(II) acetate (56 mg,0.25 mmol), xantphos (170 mg, 0.30 mmol) and cesium carbonate (375 mg,1.1 mmol) in 1,4-dioxane (15 mL) under heating at 105° C. throughmicrowave irradiation for 45 min under N₂ atmosphere. LC-MS: m/z 502.2(M+H)⁺.

Step F: A mixture of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,2,4-triazin-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine (100 mg, 0.20 mmol) in hydrogenchloride solution (4 M in dioxane, 15 mL) was stirred at roomtemperature for 4 hours. The mixture was evaporated to dryness. Theresidue was resolved in dichloromethane solution (with 10% methanol),basified with aqueous ammonia to pH 8 to afford5-(1,2,4-triazin-5-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 9.14 (s, 1H), 8.74 (s, 1H), 7.31-7.51 (m, 12H), 6.76(d, J=8.6 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 488.2 (M+H)⁺.

Compound 134:5-((4-amino-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol),1,3,5-triazine-2,4-diamine (189 mg, 1.7 mmol, 1.5 eq), Pd(OAc)₂ (38 mg,0.17 mmol, 0.15 eq), Xantphos (98 mg, 0.17 mmol, 0.15 eq) and Cs₂CO₃(360 mg, 3.34 mmol, 3.0 eq) in 1.4-dioxane (15 mL) under heating at 105°C. through microwave irradiation for 1 hour under N₂ atmosphere. LC-MS:m/z 516.9 (M+H)⁺.

Step F: A solution of5-((4-amino-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(156 mg, 0.3 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30° C.for 5 hours. The reaction mixture was concentrated in vacuum to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 13.80 (s, 1H), 8.17 (s, 2H), 7.66 (s, 1H), 7.51 (m,4H), 7.38 (dd, J=9.8, 6.1 Hz, 7H), 7.33 (d, J=8.0 Hz, 2H), 7.03 (d,J=8.4 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 503.0 (M+H)⁺.

Compound 135:6-(4-methoxyphenyl)-5-((4-(methylamino)-1,3,5-triazin-2-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (249 mg, 0.57 mmol),N2-methyl-1,3,5-triazine-2,4-diamine (106 mg, 0.85 mmol, 1.5 eq.),Pd(OAc)₂ (64 mg, 0.28 mmol, 0.5 eq.), Xantphos (197 mg, 0.34 mmol, 0.6eq.) and Cs₂CO₃ (370 mg, 1.13 mmol, 2.0 eq.) in 1.4-dioxane (10 mL)under heating at 100° C. through microwave irradiation for 1 hour underN₂ atmosphere. LC-MS: m/z 531.0 (M+H)⁺.

Step F: A solution ofN²-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-N4-methyl-1,3,5-triazine-2,4-diamine(100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at r.t.for 6 hours to afford the title compound.

¹H NMR (DMSO-d₆&TRIFLUOROACETIC ACID-d (v: 1/5)): δ 8.40 (s, 1H), 7.55(d, J=6.2 Hz, 2H), 7.33-7.47 (m, 10H), 7.04 (d, J=8.6 Hz, 2H), 3.84 (s,3H), 2.08 (s, 3H). LC-MS: m/z 517.0 (M+H)⁺.

Compound 136:5-((4-hydroxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:5-((4-methoxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(1.0 g, 2.26 mmol), 4-methoxy-1,3,5-triazin-2-amine (424.7 mg, 3.39mmol), palladium diacetate (253.7 mg, 1.13 mmol), Xantphos (784.6 mg,1.36 mmol) and sodium carbonate (383.3 mg, 3.62 mmol) in 1,4-dioxane (40mL) was refluxed for 12 hours under nitrogen atmosphere. After coolingto room temperature, the mixture was filtered with celite, diluted withDCM (150 mL), washed with saturated brine (50 mL), dried over anhydroussodium sulfate and concentrated to drynesss. The residue was purified toobtain5-((4-methoxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneas yellow solid. LC-MS: m/z 518.2 (M+H)⁺.

Step B:5-((4-hydroxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of5-((4-methoxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(350 mg, 0.68 mmol) in 4M HCl in 1.4-dioxane (40 mL) was stirred at r.t.for 16 hours. The mixture was concentrated, and saturated NaHCO₃(10 mL)was added to obtain5-((4-hydroxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 8.07 (br. s., 1H), 7.47 (br. s., 3H), 7.16-7.43 (m,15H), 6.94 (br. s., 2H), 3.78 (s, 3H). LC-MS: m/z 504.3 (M+H)⁺.

Compound 137:6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol), thiazol-2-amine(100 mg, 1.0 mmol, 2 eq.), Pd(OAc)₂ (56 mg, 0.25 mmol, 0.5 eq.),Xantphos (174 mg, 0.3 mmol, 0.6 eq.) and Na₂CO₃ (117 mg, 1.1 mmol, 2.2eq.) in 1.4-dioxane (5 mL) under heating at 100° C. for 3 h under N₂atmosphere. LC-MS: m/z 506.1 (M+H)⁺.

Step F: The solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)thiazol-2-amine(110 mg, 0.23 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t.for 10 h to afford the title compound.

¹H NMR (DMSO-d₆): δ 10.39 (br. s., 1H), 7.47-7.58 (m, 4H), 7.35-7.46 (m,6H), 7.27-7.35 (m, 3H), 7.21 (d, J=3.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H),3.83 (s, 3H). LC-MS: m/z 491.9 (M+H)⁺.

Compound 138:5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (400 mg, 0.9 mmol),isoxazol-3-amine (150 mg, 1.8 mmol, 2 eq.), Pd(OAc)₂ (20 mg, 0.09 mmol,0.1 eq.), Xantphos (104 mg, 0.18 mmol, 0.2 eq.) and Na₂CO₃ (190 mg, 1.8mmol, 2 eq.) in 1.4-dioxane (5 mL) under heating at 100° C. for 16 hoursunder N₂ atmosphere. LC-MS: m/z 490.5 (M+H)⁺.

Step F: A solution of5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(90 mg, 0.17 mmol) in 4M HCl in 1.4-dioxane (3 mL) was stirred at r.t.for 2 hours. Solvent and volatile were removed in vacuo. The mixture wasbasified with NaHCO₃ solution to PH=8 and concentrated in vacuo to givethe the title compound

¹H NMR (DMSO-d₆): δ 12.01 (s, 1H), 9.39 (s, 1H), 8.75 (d, J=1.9 Hz, 1H),7.45-7.52 (m, 3H), 7.36-7.45 (m, 6H), 7.30-7.36 (m, J=8.6 Hz, 2H),6.99-7.10 (m, J=8.9 Hz, 2H), 6.49 (d, J=1.9 Hz, 1H), 3.83 (s, 3H).LC-MS: m/z 476.5 (M+H)⁺.

Compound 139:5-(isoxazol-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (150 mg, 0.34 mmol) andisoxazol-4-amine (57 mg, 0.68 mmol, 2.0 eq), Pd(OAc)₂ (16 mg, 0.07 mmol,0.2 eq), Xantphos (41 mg, 0.07 mmol, 0.2 eq) and Cs₂CO₃ (442 mg, 1.36mmol, 4.0 eq) in 1.4-dioxane (10 mL) under heating at 100° C. throughmicrowave irradiation for 1 hour under N₂ atmosphere. LC-MS: m/z 490.2(M+H)⁺.

Step F: A solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-4-amine(38 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30° C.for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 9.24 (br. s., 1H), 8.74 (br. s., 1H), 7.98 (br. s.,1H), 7.31-7.45 (m, 6H), 7.09-7.31 (m, 9H), 7.04 (br. s., 2H), 3.81 (br.s., 3H). LC-MS: m/z 476.1 (M+H)⁺.

Compound 140:5-(isoxazol-5-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of intermediate 5 (100 mg, 0.22 mmol), isoxazol-5-amine (23mg, 0.27 mmol, 1.2 eq.), Pd(OAc)₂ (20 mg, 0.09 mmol, 0.4 eq.), Xantphos(53 mg, 0.09 mmol, 0.4 eq.) and K₂CO₃ (63 mg, 0.45 mmol, 2.5 eq.) indioxnae (4 mL) was stirred at 100° C. through microwave irradiation for1 hour under N₂ atmosphere. The mixture was filtered through celite andthe filtrate was concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 12.38 (br. s., 1H), 10.40 (br. s., 1H), 7.24-7.54(m, 15H), 7.00 (d, J=8.1 Hz, 2H), 3.81 (s, 3H). LC-MS: m/z 475.9 (M+H)⁺.

Compound 141:6-(4-methoxyphenyl)-5-(1-methyl-1H-imidazol-2-ylamino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (100 mg, 0.226 mmol),1-methyl-1H-imidazol-2-amine (33 mg, 0.340 mmol),tris(dibenzylideneacetone)dipalladium (0) (206 mg, 0.226 mmol), xantphos(130 mg, 0.226 mmol) and sodium carbonate (48 mg, 0.515 mmol) in1,4-dioxane (5 mL) under heating at 110° C. through microwaveirradiation for 1 hour under N₂ atmosphere. LC-MS: m/z 503.2 (M+H)⁺.

Step F: A mixture of7-methoxy-6-(4-methoxyphenyl)-N-(1-methyl-1H-imidazol-2-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 1 mmol) in hydrogen chloride solution (4 M in dioxane, 10 mL)was stirred at 70° C. for 16 h. The mixture was evaporated to dryness.The residue was resolved in dichloromethane solution (with 10% methanol)and washed with aqueous sodium bicarbonate to pH 8. The organic phasewas dried over sodium sulfate to afford6-(4-methoxyphenyl)-5-(1-methyl-1H-imidazol-2-ylamino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 7.49-7.31 (m, 14H), 6.99 (d, J=7.63 Hz, 2H), 3.78(s, 3H), 3.52 (s, 3H). LC-MS: m/z 489.2 (M+H)⁺.

Compound 142:5-((1H-imidazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol),1H-imidazol-2-amine (83 mg, 1 mmol, 2 eq.), Pd₂(dba)₃ (91.5 mg, 0.1mmol, 0.1 eq.), Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na₂CO₃ (212mg, 2 mmol, 2 eq.) in toluene (40 mL) under heating at 105° C. for 5hour under N₂ atmosphere. LC-MS: m/z 489.5 (M+H)⁺.

Step F: A solution ofN-(1H-imidazol-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(40 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at r.t.for 16 hours. Solvent and volatile were removed in vacuo. The resultantresidue was basified with NaHCO₃ solution to pH=8 and concentrated toafford the title compound.

¹H NMR (DMSO-d₆): δ 12.73 (br. s., 1H), 7.51 (br. s., 2H), 7.39-7.48 (m,6H), 7.21-7.39 (m, 3H), 7.06 (s, 3H), 3.81 (s, 3H). LC-MS: m/z 475.5(M+H)⁺.

Compound 143:5-((4,5-dihydrothiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol), thiazol-2-amine(102 mg, 1 mmol, 2 eq.), Pd₂(dba)₃ (91.5 mg, 0.1 mmol, 0.1 eq.),Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na₂CO₃ (212 mg, 2 mmol, 2eq.) in toluene (40 mL) under heating at 105° C. for 5 hour under N₂atmosphere. LC-MS: m/z 506.5 (M+H)⁺.

Step F: A solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)thiazol-2-amine(40 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at r.t.for 16 hours. Solvent and volatile were removed in vacuo. The resultantresidue was basified with NaHCO₃ solution to pH=8 and concentrated toafford the title compound.

¹H NMR (DMSO-d₆): δ 7.31-7.49 (m, 9H), 7.26 (d, J=8.5 Hz, 3H), 6.94 (br.s., 2H), 3.78 (s, 3H), 3.60 (br. s., 1H), 3.50 (br. s., 1H), 3.31 (br.s., 2H). LC-MS: m/z 494.5 (M+H)⁺.

Compound 144:5-((1,3,4-thiadiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (442 mg, 1.0 mmol) and1,3,4-thiadiazol-2-amine (101 mg, 1.0 mmol, 1 eq) and Pd(OAc)₂ (91.5 mg,0.1 mmol, 0.1 eq), Xant-phos (115.6 mg, 0.2 mmol, 0.2 eq) and Na₂CO₃(212 mg, 2.0 mmol, 2.0 eq) in toluene (40 mL) under heating at 110° C.for 5 hour under N₂ atmosphere. LC-MS: m/z 507.1 (M+H)⁺.

Step F: A mixture ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,4-thiadiazol-2-amine(112 mg, 0.2 mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at roomtemperature overnight. The reaction mixture was concentrate in vacuo.The residue was stirred with methanol and saturated sodium hydrogencarbonate solution to afford the title compound.

¹H NMR (DMSO-d₆): δ 13.83 (br. s., 1H), 10.57 (br. s., 1H), 9.05 (br.s., 1H), 7.54 (br. s., 4H), 7.42 (br. s., 5H), 7.34 (br. s., 3H), 7.08(d, J=7.79 Hz, 2H), 3.85 (s, 3H). LC-MS: m/z 493.1 (M+H)⁺.

Compound 145:5-((5-amino-1,3,4-thiadiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (600 mg, 1.36 mmol) and1,3,4-thiadiazole-2,5-diamine (315 mg, 2.72 mmol, 2 eq.), Pd(OAc)₂ (306mg, 0.1.36 mmol, 1 eq.), Xantphos (786 mg, 1.36 mmol, 1 eq.) and Cs₂CO₃(887 mg, 2.72 mmol, 2.0 eq.) in 1.4-dioxane (18 mL) under heating at120° C. through microwave irradiation for 1 hour under N₂ atmosphere.LC-MS: m/z 522.0 (M+H)⁺.

Step F: A solution ofN2-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,4-thiadiazole-2,5-diamine(100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at r.t.overnight. Solvent and volatile were removed in vacuo. The residue wasdissolved in DCM (5 mL) and basified with saturated NaHCO₃. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 9.96 (br. s., 1H), 7.37-7.57 (m, 9H), 7.32-7.37 (m,1H), 7.29 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.6 Hz, 2H), 3.82 (s, 3H).LC-MS: m/z 508.0 (M+H)⁺.

Compound 146:5-((5-hydroxy-1,3,4-thiadiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (442 mg, 1.0 mmol) and5-methoxy-1,3,4-thiadiazol-2-amine (113 mg, 1.0 mmol, 1 eq), Pd(OAc)₂(91.5 mg, 0.1 mmol, 0.1 eq), Xant-phos (115.6 mg, 0.2 mmol, 0.2 eq) andNa₂CO₃ (212 mg, 2.0 mmol, 2.0 eq) in toluene (40 mL) under heating at110° C. for 5 hour under N₂ atmosphere. LC-MS: m/z 537.1 (M+H)⁺.

Step F: A mixture of5-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,4-thiadiazol-2-amine(51.8 mg, 0.1 mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo.The residue was stirred with methanol and saturated sodium hydrogencarbonate solution to afford the title compound.

¹H NMR (DMSO-d₆): δ 12.43 (s, 0.5H), 12.12 (s, 0.5H), 11.87 (s, 0.5H),9.80 (s, 0.5H), 7.50 (br. s., 3H), 7.41 (br. s., 4H), 7.30 (br. s., 4H),7.04 (d, J=8.55 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 509.1 (M+H)⁺.

Compound 147:5-((1,2,4-thiadiazol-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (600 mg, 1.3 mmol) and1,2,4-thiadiazol-5-amine (179 mg, 1.77 mmol, 1.3 eq), Pd(OAc)₂ (46 mg,0.2 mmol, 0.15 eq), Xantphos (118 mg, 0.2 mmol, 0.15 eq) and Cs₂CO₃ (844mg, 2.72 mmol, 2.0 eq) in 1.4-dioxane (15 mL) under heating at 100 Cthrough microwave irradiation for 1 hour under N₂ atmosphere. LC-MS: m/z506.9H).

Step F: A solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,4-thiadiazol-5-amine(214 mg, 0.42 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆) δ: 10.13 (s, 1H), 8.21 (s, 1H), 7.55 (dd, J=7.6, 1.6Hz, 2H), 7.53-7.38 (m, 8H), 7.35 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz,2H), 6.28 (s, 2H), 3.84 (s, 3H). LC-MS: m/z 492.9 (M+H)⁺.

Compound 148:5-((3-methoxy-1,2,4-thiadiazol-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (400 mg, 0.91 mmol) and3-methoxy-1,2,4-thiadiazol-5-amine (155 mg, 1.18 mmol, 1.3 eq), Pd(OAc)₂(11 mg, 0.14 mmol, 0.15 eq), Xantphos (78.7 mg, 0.14 mmol, 0.15 eq) andCs₂CO₃ (590 mg, 1.8 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heatingat 110° C. through microwave irradiation for 1 hour under N₂ atmosphere.LC-MS: m/z 537.0 (M+H)⁺.

Step F: A solution of3-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,4-thiadiazol-5-amine(100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 10.27 (s, 1H), 7.57-7.52 (m, 2H), 7.51-7.36 (m, 8H),7.31 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 3.82 (s, 6H). LC-MS: m/z523.0 (M+H)⁺.

Compound 149:5-((4-amino-1,2,5-oxadiazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol),N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,5-oxadiazole-3,4-diamine(101 mg, 1.0 mmol, 2.0 eq), Pd(OAc)₂ (11 mg, 0.05 mmol, 0.1 eq),Xantphos (116 mg, 0.2 mmol, 0.4 eq) and Cs₂CO₃ (325 mg, 1.0 mmol, 2.0eq) in 1.4-dioxane (10 mL) under heating at 100° C. through microwaveirradiation for 1 hour under N₂ atmosphere. LC-MS: m/z 506.1 (M+H)⁺.

Step F: A solution ofN3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,5-oxadiazole-3,4-diamine(237 mg, 0.47 mmol) in 4M HCl in 1.4-dioxane (20 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 8.51 (br. s., 1H), 7.25-7.55 (m, 12H), 7.00 (d,J=8.8 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 492.1 (M+H)⁺.

Compound 150: ethyl5-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate

Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), ethyl5-aminothiazole-4-carboxylate (292.3 mg, 1.70 mmol), and Pd(OAc)₂ (76.2mg, 0.34 mmol), Xantphos (196.4 mg, 0.34 mmol) and Cs₂CO₃ (553.0 mg,0.34 mmol) in 1.4-dioxane (10 mL) under heating at 120° C. throughmicrowave irradiation for 1.5 hours under N₂ atmosphere. LC-MS: m/z578.3 (M+H)⁺.

Step F: A solution of ethyl5-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate(450 mg, 0.78 mmol) in 4M HCl in 1.4-dioxane (16 mL) was stirred at r.t.for 18 hours. The mixture was concentrated, and saturated NaHCO₃(10 mL)was added to obtain ethyl5-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate.

¹H NMR (DMSO-d₆): δ 10.03 (s, 1H), 8.30 (s, 1H), 7.50-7.63 (m, 4H),7.29-7.45 (m, 7H), 7.14-7.26 (m, 1H), 7.04 (d, J=8.9 Hz, 2H), 4.12 (q,J=7.0 Hz, 2H), 3.83 (s, 3H), 1.17 (t, J=7.1 Hz, 3H). LC-MS: m/z 564.3(M+H)⁺.

Compound 151:5-((1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry: Intermediate 5 (200 mg, 0.450 mmol),1H-pyrrolo[2,3-c]pyridin-5-amine (120 mg, 0.90 mmol), palladium(II)acetate (50 mg, 0.225 mmol), xantphos (196 mg, 0.340 mmol) and potassiumcarbonate (124 mg, 0.90 mmol) in 1,4-dioxane (10 mL) under heating at100° C. through microwave irradiation for 1 hour under N₂ atmosphere.LC-MS: m/z 539.2 (M+H)⁺.

Step F: A mixture of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1H-pyrrolo[2,3-c]pyridin-5-yl)-pyrazolo[1,5-a]pyrimidin-5-amine(80 mg, 0.148 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL)was stirred at room temperature for 16 hours. The mixture was evaporatedto dryness. The residue was resolved in dichloromethane solution (with10% methanol) and basified with aqueous ammonia to pH 8 to afford5-(1H-pyrrolo[2,3-c]pyridin-5-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 16.31 (s, 1H), 11.56 (s, 1H), 8.61 (s, H), 8.25 (s,1H), 7.72-7.35 (m, 14H), 7.07 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 3.85 (s,1H). LC-MS: m/z 525.2 (M+H)⁺.

5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

This compound was prepared according to the procedure for preparingcompound 101 by using Intermediate 8 as4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B: To a solution of dimethyl 2-(4-methoxyphenyl)malonate (39.6 g,166 mmol) in tri-n-butylamine (80 ml) at 198° C. was added4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (47.3 g, 199 mmol) inportions, and the resultant mixture was stirred for 1 h at 198° C. Themixture was cooled to the room temperature, and solvent was decanted.THF (150 mL) and HCl (6N, 600 mL) were added with stirring vigorouslyfor 0.5 h. The precipitates were collected by filtration, washed withmethanol, and dried under reduced pressure to give3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(48 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 7.74 (d, J=6.98 Hz, 2H), 7.31-7.49 (m, 5H), 6.94 (d,J=8.60 Hz, 2H), 5.80 (br. s., 1H), 3.78 (s, 3H), 2.15 (br. s., 2H), 2.02(br. s., 2H), 1.65 (br. s., 4H). LC-MS: m/z 414.2 (M+H)⁺.

Step C: A solution of3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(47.0 g, 104 mmol) in phosphorus oxychloride (100 mL) was stirred atreflux for 16 hrs. The solvent was removed in vacuum. The residue wasadded slowly to methanol (100 mL) cooled at 0° C. The precipitates werecollected by filtration, washed with methanol, and dried under reducedpressure to give5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(50 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 7.82 (d, J=7.25 Hz, 2H), 7.36-7.56 (m, 5H), 7.10 (d,J=8.60 Hz, 2H), 5.87 (br. s., 1H), 3.84 (s, 3H), 2.20 (br. s., 4H), 1.70(d, J=4.57 Hz, 4H). LC-MS: m/z 450.2 (M+H)⁺.

Step D: To a solution of5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(40 g, 88 mmol) in dichloromethane (400 ml) at 0° C. was added sodiummethoxide (30% in methanol, 80 g) dropwise. The resultant mixture wasstirred for 10 min at 0° C. The reaction was quenched by adding icewater (100 mL) and extracted with dichloromethane (200 mL) three times.The combined organic layers were washed with brine (200 ml), dried overanhydrous sodium sulfate, and concentrated in vacuum. The residue wassuspended in MeOH (50 mL). The precipitates were collected byfiltration, washed with MeOH, and dried under reduced pressure to give5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidineas a yellow solid.

¹H NMR (DMSO-d₆): δ 7.78-7.91 (m, 2H), 7.42-7.58 (m, 3H), 7.33-7.42 (m,J=8.9 Hz, 2H), 7.00-7.14 (m, J=8.9 Hz, 2H), 5.83 (br. s., 1H), 4.14 (s,3H), 3.84 (s, 3H), 2.20 (d, J=5.9 Hz, 4H), 1.61-1.77 (m, 4H). LC-MS: m/z446.1 (M+H)⁺.

6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline

This compound was prepared according to the procedure for preparingcompound 101 by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetatein step A.

Step A: To dimethyl carbonate (150 mL) cooled at 0° C. was addedpotassium tert-butanolate (24 g, 216 mmol) in portions. The resultantmixture was stirred at 0° C. for 1 hour. Methyl 2-(quinolin-6-yl)acetate(20 g, 100 mmol) was added. The resultant mixture was slowly warmed upto room temperature and stirred for 1 hour. The reaction mixture washeated to 80° C. with stirring overnight. After cooling to roomtemperature, the mixture was diluted with EtOAc (1500 mL), washed withsaturated NH₄Cl (300 mL) and brine (250 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by flashcolumn (petroleum ether/ethyl acetate=3:1) to obtain dimethyl2-(quinolin-6-yl)malonate (18.0 g) as a yellow solid. LC-MS: m/z 260.1(M+H)+.

Step B: A suspension of dimethyl 2-(quinolin-6-yl)malonate (13 g, 50mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (11.8 g, 50 mmol) intributylamine (100 mL) was stirred at 185° C. for 4 hours. After coolingto room temperature, the mixture was filtered. The residue was dilutedwith DCM (450 mL), washed with saturated NH₄Cl (150 ml) and brine (100ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash column (DCM:MeOH=15:1) to obtain2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(18 g) as a yellow solid. LC-MS: m/z 431.2 (M+H)⁺.

Step C: The solution of2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(18 g, 42 mmol), DMAP (1 g) and PCl₅ (80 mg) in POCl₃ (180 ml) wasstirred at 100° C. overnight. After cooling to room temperature, thesolvent was removed by vacuum. The residue was cooled to 0° C. MeOH (60mL) was added to quench the reaction. The resultant mixture was dilutedwith DCM (450 ml), washed with saturated NaHCO₃(150 ml) and brine (100ml), dried over anhydrous sodium sulfate, and concentrated to affordcrude product of6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline (13g) which was used in the next step without further purification. LC-MS:m/z 467.1 (M+H)⁺.

Step D: To a solution of6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(13.0 g, crude, 27.8 mmol) in DCM/MeOH (200 mL, 1:1) cooled at 0° C. wasadded sodium methoxide (14.9 mL, 5.0 M in methanol) dropwise. Then themixture was stirred at 0° C. for 1 hour. Saturated NH₄Cl (150 mL) wasadded to quench the reaction. The resultant mixture was extracted withDCM (500 mL), washed with brine (150 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn (DCM/MeOH=40:1) to obtain6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolineas a pale yellow solid.

¹H NMR (DMSO-d₆): δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.45-8.52 (m, 1H),8.13-8.21 (m, 2H), 7.88 (dd, J=8.6, 1.9 Hz, 1H), 7.59-7.68 (m, 3H),7.42-7.48 (m, 7H), 7.34-7.41 (m, 1H), 4.25 (s, 3H). LC-MS: m/z 463.1(M+H)+.

6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline

This compound was prepared according to the procedure for preparingcompound 101 by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetatee in step A and Intermediate 8 as4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B: A suspension of dimethyl 2-(quinolin-6-yl)malonate (1.95 g, 7.52mmol) and 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (1.8 g,7.52 mmol) in tributylamine (20 mL) was stirred at 185° C. for 4 hours.After cooling to room temperature, the mixture was filtered. The residuewas diluted with DCM (150 mL), washed with saturated NH₄Cl (50 ml) andbrine (50 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by flash column (DCM:MeOH=15:1) toobtain3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(3.1 g) as a yellow solid. LC-MS: m/z 435.2 (M+H)⁺.

Step C: The solution of3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(3.1 g, 7.13 mmol) in POCl₃ (12 ml) was stirred at 110° C. overnight.After cooling to room temperature, the solvent was removed by vacuum.MeOH (60 mL) was added slowly to the residue cooled at 0° C. to quenchthe reaction. The resultant mixture was diluted with DCM (150 ml),washed with saturated NaHCO₃(50 ml) and brine (50 ml), dried overanhydrous sodium sulfate, and concentrated to afford crude product of6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(1.3 g) which was used in the next step without further purification.LC-MS: m/z 471.9 (M+H)⁺.

Step D: To a solution of6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(300 mg, crude, 0.64 mmol) in DCM/MeOH (6 mL, 1:1) cooled at 0° C. wasadded sodium methoxide (0.64 mL, 5.0 M in methanol) dropwise. Then themixture was stirred at 0° C. for 1 hour. Saturated NH₄Cl (50 mL) wasadded to quench the reaction. The resultant mixture was extracted withDCM (150 mL), washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn (DCM/MeOH=40:1) to obtain6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolineas a off-white solid.

¹H NMR (CHLOROFORM-d): δ 9.28 (d, J=3.8 Hz, 1H), 8.76 (d, J=8.6 Hz, 2H),8.11 (s, 1H), 7.80-8.03 (m, 4H), 7.36-7.57 (m, 3H), 5.99 (br. s., 1H),3.75 (s, 3H), 2.20-2.37 (m, 4H), 1.67-1.87 (m, 4H). LC-MS: m/z 467.2(M+H)⁺.

6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline

This compound was prepared according to the procedure for preparingcompound 101 by using Intermediate 1 as methyl2-(quinoxalin-6-yl)acetate in step A and Intermediate 8 as4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step A: To dimethyl carbonate (30 mL) cooled at 0° C. was addedpotassium tert-butanolate (3.8 g, 34.12 mmol) in portions. The resultantmixture was stirred at 0° C. for 1 hour. Methyl2-(quinoxalin-6-yl)acetate (2.3 g, 11.37 mmol) was added. The resultantmixture was slowly warmed up to room temperature and stirred for 1 hour.The reaction mixture was heated to 90° C. and stirred for 1.5 hours.After cooling to room temperature, the mixture was diluted with EtOAc(150 mL), washed with saturated NH₄Cl (80 mL) and brine (50 mL), driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by flash column (petroleum ether/ethyl acetate=3:1) to obtaindimethyl 2-(quinoxalin-6-yl)malonate (2.0 g) as a yellow solid.

¹H NMR (CHLOROFORM-d): δ 8.89 (s, 2H), 8.10-8.19 (m, 2H), 7.91 (dd,J=8.7, 2.0 Hz, 1H), 4.95 (s, 1H), 3.82 (s, 6H). LC-MS: m/z 261.1 (M+H)⁺.

Step B: A suspension of4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (1.93 g, 8.07 mmol)and dimethyl 2-(quinoxalin-6-yl)malonate (2.1 g, 8.07 mmol) intributylamine (20 mL) was stirred at 175° C. for 2 hours. After coolingto room temperature, the mixture was filtered. The residue was dilutedwith DCM (150 mL), washed with saturated NH₄Cl (50 ml) and brine (30ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash column (DCM:MeOH=15:1) to obtain3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(2.2 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 10.11 (br. s., 1H), 9.07 (br. s., 1H), 8.79 (s, 1H),8.73 (s, 1H), 8.58 (s, 1H), 8.51 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.9 Hz,1H), 7.71 (d, J=7.3 Hz, 2H), 7.27-7.46 (m, 3H), 5.69 (br. s., 1H), 2.14(br. s., 2H), 2.00 (br. s., 2H), 1.60-1.68 (m, 4H). LC-MS: m/z 436.2(M+H)⁺.

Step C: The solution of3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(1.0 g, 2.30 mmol) in POCl₃ (6 ml) in a sealed tube was stirred at 110°C. for 8 hours. After cooling to room temperature, the solvent wasremoved by vacuum. The residue was cooled to 0° C. MeOH (6 mL) was addedto quench the reaction. The resultant mixture was diluted with DCM (150ml), washed with saturated NaHCO₃ (50 ml) and brine (30 ml), dried overanhydrous sodium sulfate, and concentrated to afford crude product of6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline(800 mg) which was used in the next step without further purification.LC-MS: m/z 472.1 (M+H)⁺.

Step D: To a solution of6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline(800 mg, crude, 2.30 mmol) in DCM/MeOH (20 mL, 1:1) cooled at 0° C. wasadded sodium methoxide (2.3 mL, 5.0 M in methanol) dropwise. Then themixture was stirred at 0° C. for 1 hour. Saturated NH₄Cl (50 mL) wasadded to quench the reaction. The resultant mixture was extracted withDCM (100 mL), washed with brine (30 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn (DCM/MeOH=40:1) to obtain6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxalineas a brown solid.

¹H NMR (CHLOROFORM-d): δ 8.98 (s, 2H), 8.29 (d, J=8.9 Hz, 1H), 8.24 (d,J=1.6 Hz, 1H), 7.92 (dd, J=7.9, 1.5 Hz, 2H), 7.86 (dd, J=8.6, 1.9 Hz,1H), 7.41-7.55 (m, 3H), 5.98 (dt, J=3.6, 1.9 Hz, 1H), 4.26-4.37 (m, 3H),2.33 (br. s., 2H), 2.19-2.30 (m, 2H), 1.71-1.85 (m, 4H). LC-MS: m/z468.2 (M+H)⁺.

The following compounds were prepared according to Example 1, step E andF, starting from5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

Compound 153:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(200 mg, 0.0449 mol), pyridin-2-amine (63.4 m g, 0.674 mol, 1.5 eq.),Pd(OAc)₂ (20.2 mg, 0.0898 mol, 0.2 eq.), Xantphos (52 mg, 0.0898 mol,0.2 eq.) and K₂CO₃ (265 mg, 1.12 mol, 2.5 eq.) in dioxnae (5 mL) underheating at 120° C. for 1 hour under N₂ atmosphere. LC-MS: m/z 504.9(M+H)⁺.

Step F: A solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(120 mg, 0.22 mol) in 4M HCl/1.4-dioxane (3 mL) was stirred at r.t. for16 hours. The reaction mixture was basified with NaHCO₃ solution to pH=8and filtered to afford the title compound.

¹H NMR (DMSO-d₆): δ 9.09 (br. s., 1H), 8.20 (d, J=4.3 Hz, 1H), 7.82 (t,J=7.3 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.38-7.51 (m, 3H), 7.28-7.38 (m,3H), 7.10-7.17 (m, 1H), 7.03 (d, J=8.5 Hz, 2H), 6.06 (br. s., 1H), 3.82(s, 3H), 2.34 (br. s., 2H), 2.06 (br. s., 2H), 1.65-1.79 (m, 4H). LC-MS:m/z 490.2 (M+H)⁺.

Compound 154:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(200 mg, 0.45 mmol), pyridin-3-amine (85 mg, 0.90 mmol), Pd(OAc)₂ (36mg, 0.045 mmol), xantphos (58 mg, 0.09 mmol), and CS₂CO₃ (293 mg, 0.90mmo) in dioxane (20 mL) under heating at 110° C. for 4 hours under N₂atmosphere. LC-MS: m/z 504.2 (M+H)⁺.

Step F: To a solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(60 mg, 0.12 mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane(10 mL). The reaction mixture was heated to 50° C. for 2 h. The mixturewas concentrated in vacuo. The crude product was basified with saturatedNaHCO₃ solution to give the desired product3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 8.69 (br. s., 1H), 8.31 (d, J=5.4 Hz, 1H), 8.17 (d,J=8.3 Hz, 1H), 7.71-7.83 (m, 3H), 7.39-7.52 (m, 3H), 7.24-7.33 (m, J=8.6Hz, 2H), 6.81-6.94 (m, J=8.9 Hz, 2H), 5.88 (br. s., 1H), 3.73 (s, 3H),2.14 (br. s., 2H), 2.02-2.12 (m, 2H), 1.56-1.74 (m, 4H). LC-MS: m/z490.2 (M+H)⁺.

Compound 155:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyrimidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(400 mg, 0.897 mmol) and pyrimidin-4-amine (255.9 mg, 2.691 mmol, 3 eq),Pd(OAc)₂ (40.3 mg, 0.179 mmol, 0.2 eq), Xant-phos (578.6 mg, 0.359 mmol,0.4 eq) and Cs₂CO₃ (285.2 mg, 2.691 mmol, 3 eq) in 1.4-dioxane (10 mL)under heating at 100° C. through microwave irradiation for 1 hour underN₂ atmosphere. LC-MS: m/z 505.0 (M+H)⁺.

Step F: A solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(100 mg, 0.198 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred atroom temperature for 3 hours. The reaction mixture was concentrated invacuo. The residue was dissolved in 7N NH₃ in methanol and stirred atroom temperature for 2 hours to afford the title compound.

¹H NMR (DMSO-d₆): δ 8.98 (s, 1H), 8.49 (d, J=7.02 Hz, 1H), 7.79 (d,J=7.32 Hz, 2H), 7.41-7.52 (m, 3H), 7.27 (m, J=8.54 Hz, 2H), 7.18 (d,J=6.41 Hz, 1H), 6.93 (m, J=8.54 Hz, 2H), 5.87 (br. s., 1H), 2.18 (br.s., 2H), 2.06 (br. s., 2H), 1.67 (br. s., 4H). LC-MS: m/z 491.0 (M+H)⁺.

Compound 156:3-cyclohexenyl-6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2-phenyl-pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(200 mg, 0.452 mmol) and 2-methoxypyrimidin-4-amine (113 mg, 0.904 mmol)and Pd(OAc)₂ (31 mg, 0.136 mmol), Xantphos (157 mg, 0.272 mmol) andNa₂CO₃ (96 g, 0.904 mmol) in 1.4-dioxane (10 mL) under heating at 110°C. for 4 hours under N₂ atmosphere.

¹HNMR (DMSO-d₆) δ 8.46 (d, J=5.6 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 7.81d, J=7.2 Hz, 2H), 7.56 (s, 1H), 7.42-7.51 (m, 4H), 7.16-7.18 (m, 2H),5.88 (bs, 1H), 4.11 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 2.22-2.27 (m,4H), 1.70-1.75 (m, 4H). LC-MS: m/z 535.2 (M+H)⁺.

Step F: A mixture of3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxy-pyrimidin-4-yl)-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-amine(55 mg, 0.103 mmol) and HCl solution (4N in dioxane, 6 mL) was stirredat room temperature overnight. The mixture was quenched with NH₃solution (7N in methanol) to pH 7 to afford3-cyclohexenyl-6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2-phenyl-pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.82 (s, 1H), 9.38 (s, 1H), 8.28 (d, J=5.80 Hz,1H), 7.75 (d, J=7.32 Hz, 2H), 7.45-7.51 (m, 2H), 7.42 (d, J=7.32 Hz,1H), 7.29 (m, J=8.54 Hz, 2H), 7.02 (m, J=8.85 Hz, 2H), 6.86 (d, J=5.80Hz, 1H), 5.99 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.28 (bs, 2H) 2.06(bs, 2H), 1.70 (bs, 4H). LC-MS: m/z 521.5 (M+H)⁺.

Compound 157:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridazin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(150 mg, 0.34 mmol) and pyridazin-3-amine (65 mg, 0.68 mmol, 2.0 eq),Pd(OAc)₂ (16 mg, 0.07 mmol, 0.2 eq), Xantphos (41 mg, 0.07 mmol, 0.2 eq)and Cs₂CO₃ (442 mg, 1.36 mmol, 4.0 eq) in 1.4-dioxane (10 mL) underheating at 100° C. for 1 hour through microwave irradiation undernitrogen atmosphere. LC-MS: m/z 504.9 (M+H)⁺.

Step F: A solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(70 mg, 0.14 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 15.09 (s, 1H), 9.18 (s, 1H), 8.92 (d, J=2.8 Hz, 1H),7.74 (d, J=7.2 Hz, 2H), 7.66 (d, J=6.0 Hz, 2H), 7.46-7.53 (m, 2H), 7.43(d, J=7.6 Hz, 1H), 7.30-7.39 (m, J=8.6 Hz, 2H), 6.98-7.11 (m, J=8.6 Hz,2H), 6.07 (br. s., 1H), 3.83 (s, 3H), 2.32-2.38 (m, 2H), 2.07 (br. s.,2H), 1.70 (br. s., 4H). LC-MS: m/z 491.1 (M+H)⁺.

Compound 158:3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(200 mg, 0.450 mmol) and pyrazin-2-amine (86 mg, 0.900 mmol, 2 eq) andpalladium(II) acetate (111 mg, 0.495 mmol, 1.1 eq), Xantphos (312 mg,0.540 mmol, 1.2 eq) and sodium carbonate (323 mg, 0.990 mmol, 2.2 eq) in1.4-dioxane (10 mL) under heating at 100° C. through microwaveirradiation for 1 hour under nitrogen atmosphere. LC-MS: m/z 505.2(M+H)⁺.

Step F: A solution of3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine (150 mg, 0.30 mmol) in 4MHCl/1.4-dioxane (5 mL) was stirred at room temperature for 24 hours. Thereaction mixture was concentrated in vacuo. The residue was dissolved indichloromethane:methanol=10:1 (10 mL) and washed with saturated sodiumcarbonate (5 mL) twice to pH 8. The organic layer was concentrated invacuo to give3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 3.90 (s, 1H), 9.35 (s, 1H), 8.64 (s, 1H), 8.25 (d,J=2.75 Hz, 1H), 8.20 (dd, J=2.75, 1.22 Hz, 1H), 7.67-7.77 (m, 2H)7.44-7.53 (m, 2H), 7.37-7.44 (m, 1H), 7.27-7.36 (m, 2H), 6.98-7.06 (m,2H), 6.04 (br. s., 1H) 3.81 (s, 3H), 2.34 (br. s., 2H), 2.05 (br. s.,2H), 1.70 (d, J=4.88 Hz, 4H). LC-MS: m/z 491.2 (M+H)⁺.

Compound 159:5-(3-cyclohexenyl-6-(4-methoxyphenyl)-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(500 mg, 1.07 mmol), 5-aminopyrazine-2-carbonitrile (257 mg, 2.15 mmol),palladium(II) acetate (48 mg, 0.214 mmol), xantphos (124 mg, 0.214 mmol)and sodium carbonate (230 mg, 0.215 mmol) in 1,4-dioxane (10 mL) underheating at 110° C. for 4 hours under nitrogen atmosphere. LC-MS: m/z530.2 (M+H)⁺.

Step F: A mixture of5-(3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile(170 mg, 0.321 mmol) in hydrogen chloride solution (4 M in dioxane, 5mL) was stirred at room temperature for 16 h. The mixture was evaporatedto dryness. The residue was resolved in dichloromethane solution (with10% methanol) and washed with aqueous sodium bicarbonate to pH 8. Theorganic phase was dried over sodium sulfate to afford5-(3-cyclohexenyl-6-(4-methoxyphenyl)-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile.

¹H NMR (DMSO-d₆): δ 12.76 (br. s., 1H), 10.15 (br. s., 1H), 8.73 (s, 1H)8.44 (br. s., 1H), 7.75 (d, J=7.02 Hz, 2H), 7.36-7.54 (m, 3H), 7.28 (m,J=8.54 Hz, 2H), 6.97 (m, J=8.55 Hz, 2H), 5.92 (br. s., 1H), 3.78 (s,3H), 2.25 (br. s., 2H), 2.04 (br. s., 2H), 1.68 (br. s., 4H). LC-MS: m/z516.2 (M+H)⁺.

Compound 160:5-((5-aminopyrazin-2-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(44 mg, 0.0998 mmol), pyrazine-2,5-diamine (30 mg, 0.204 mmol),palladium(II) acetate (22 mg, 0.0998 mmol), xantphos (70 mg, 0.121 mmol)and cesium carbonate (130 g, 0.4 mmol) in 1,4-dioxane (6 mL) underheating at 110° C. for 1 hour under nitrogen atmosphere. LC-MS: m/z520.2 (M+H)⁺.

Step F: A mixture ofN²-(3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)pyrazine-2,5-diamine(90 mg, 0.18 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL)was stirred at 50° C. for 3 hours. The mixture was evaporated todryness. The residue was resolved in dichloromethane solution (with 10%methanol), basified with aqueous ammonia to pH 8 to afford5-(5-aminopyrazin-2-ylamino)-3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.92 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.2 Hz, 1H),7.71 (d, J=7.0 Hz, 2H), 7.56 (s, 1H), 7.44-7.51 (m, 2H), 7.41 (d, J=7.3Hz, 1H), 7.27-7.33 (m, J=8.9 Hz, 2H), 7.01-7.07 (m, J=8.9 Hz, 2H), 6.23(s, 2H), 6.04 (br. s., 1H), 3.83 (s, 3H), 2.33 (br. s., 2H), 2.04 (br.s., 2H), 1.71 (br. s., 4H). LC-MS: m/z 506.2 (M+H)⁺.

Compound 161:5-((1,2,4-triazin-3-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(150 mg, 0.34 mmol) and 1,2,4-triazin-3-amine (65 mg, 0.68 mmol, 2.0eq), Pd(OAc)₂ (16 mg, 0.07 mmol, 0.2 eq), Xantphos (41 mg, 0.07 mmol,0.2 eq) and Cs₂CO₃ (442 mg, 1.36 mmol, 4.0 eq) in 1.4-dioxane (10 mL)under heating at 100° C. for 1 hour through microwave irradiation undernitrogen atmosphere. LC-MS: m/z 505.9 (M+H)⁺.

Step F: A solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1,2,4-triazin-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(30 mg, 0.06 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuum toobtain the title compound.

¹H NMR (DMSO-d₆): δ 12.81 (s, 1H), 9.78 (s, 1H), 8.92 (s, 1H), 8.51 (s,1H), 7.77 (d, J=7.2 Hz, 2H), 7.39-7.52 (m, 3H), 7.26 (d, J=8.0 Hz, 2H),6.93 (d, J=8.0 Hz, 2H), 3.76 (s, 3H), 2.21 (br. s., 2H), 2.06 (br. s.,2H), 1.66 (br. s., 4H). LC-MS: m/z 492.0 (M+H)⁺.

Compound 162:5-((1,2,4-triazin-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(110 mg, 0.25 mmol), 1,2,4-triazin-5-amine (50 mg, 0.50 mmol),palladium(II) acetate (28 mg, 0.125 mmol), xantphos (87 mg, 0.15 mmol)and cesium carbonate (180 mg, 0.55 mmol) in 1,4-dioxane (15 mL) underheating at 105° C. through microwave irradiation for 45 min undernitrogen atmosphere. LC-MS: m/z 506.2 (M+H)⁺.

Step F: A mixture of3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1,2,4-triazin-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine (50 mg, 0.10 mmol) in hydrogen chloridesolution (4 M in dioxane, 5 mL) was stirred at room temperature for 4hours. The mixture was evaporated to dryness. The residue was resolvedin dichloromethane solution (with 10% methanol), basified with aqueousammonia to pH 8 to afford5-(1,2,4-triazin-5-ylamino)-3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 9.02 (s, 1H), 8.64 (br. s., 1H), 7.77 (d, J=7.0 Hz,2H), 7.38-7.54 (m, 3H), 7.26 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H),5.85 (br. s., 1H), 3.76 (s, 3H), 2.18 (br. s., 2H), 2.05 (br. s., 2H),1.66 (br. s., 4H). LC-MS: m/z 492.2 (M+H)⁺.

Compound 163:5-((1,3,5-triazin-2-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(500 mg, 1.121 mmol) and 1,3,5-triazin-2-amine (323.2 mg, 3.364 mmol, 3eq), Pd(OAc)₂ (50.3 mg, 0.224 mmol, 0.2 eq), Xant-phos (259.5 mg, 0.453mmol, 0.4 eq) and Cs₂CO₃ (1.09 g, 3.364 mmol, 3 eq) in 1.4-dioxane (10mL) was stirred and warmed up to 100° C. through microwave irradiationfor 1 hour under N₂ atmosphere. The reaction was then cooled to roomtemperature, diluted with saturated sodium hydrogen carbonate solution,and extracted with EtOAc (20×3 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to obtain the title compound.

¹H NMR (CHLOROFORM-d): δ 12.85 (br. s., 1H), 8.85 (s, 2H), 7.88 (d,J=6.18 Hz, 2H), 7.76 (br. s., 1H), 7.35-7.48 (m, 4H), 7.08 (d, J=8.06Hz, 2H), 6.09 (br. s., 1H), 3.89 (s, 2H), 2.37 (br. s., 2H), 2.12 (br.s., 2H), 1.77 (br. s., 3H), 1.68 (br. s., 1H), 1.23-1.39 (m, 1H). LC-MS:m/z 492.0 (M+H)⁺.

Compound 164:5-((4-amino-1,3,5-triazin-2-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(222 g, 0.5 mmol), 1,3,5-triazine-2,4-diamine (83 mg, 0.75 mmol, 1.5eq.), Pd(OAc)₂ (23 mg, 0.1 mmol, 0.2 eq.), Xantphos (115 mg, 0.2 mmol,0.4 eq.) and Cs₂CO₃ (195 mg, 0.6 mmol, 12 eq.) in 1.4-dioxane (4 mL)under heating at 100° C. through microwave irradiation for 1 hour underN₂ atmosphere. LC-MS: m/z 521.0 (M+H)⁺.

Step F: The solution ofN²-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,5-triazine-2,4-diamine(80 mg, 0.15 mmol) in HCl-1,4-dioxane (5 mL). The solution was stirredat r.t. for 6 h. Solvent and volatile were removed in vacuo. The residuewas dissolved in DCM (5 mL) and treated with saturated NaHCO₃. Theorganic phase was separated and washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 8.28 (br. s., 1H), 7.74 (d, J=7.2 Hz, 2H), 7.38-7.52(m, 4H), 7.31 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 5.96 (br. s.,1H), 3.80 (s, 3H), 2.26 (br. s., 2H), 2.04 (br. s., 2H), 1.68 (br. s.,4H). LC-MS: m/z 507.0 (M+H)⁺.

Compound 165:3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(1.0 g, 2.24 mmol), isoxazol-3-amine (377.1 mg, 4.48 mmol), andpalladium diacetate (101.0 mg, 0.45 mmol), Xantphos (388.8 mg, 0.67mmol) and sodium carbonate (474.8 mg, 4.48 mmol) in 1,4-dioxane (50 mL)under heating at 110° C. for 12 hours under nitrogen atmosphere. LC-MS:m/z 494.2 (M+H)⁺.

Step F: A solution ofN-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine(450 mg, 0.91 mmol) in 4M HCl in 1.4-dioxane (40 mL) was stirred at r.t.for 2 hours. The mixture was concentrated at low temperature (<25° C.),and saturated NaHCO₃(8 mL) was added to obtain3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneas.

¹H NMR (DMSO-d₆): δ 11.97 (s, 1H), 9.40 (s, 1H), 8.79 (s, 1H), 7.72 (d,J=7.3 Hz, 2H), 7.37-7.56 (m, 3H), 7.23-7.37 (m, J=8.5 Hz, 2H), 6.98-7.13(m, J=8.5 Hz, 2H), 6.51 (s, 1H), 6.03 (br. s., 1H), 3.82 (s, 3H), 2.28(br. s., 2H), 2.03 (br. s., 2H), 1.68 (br. s., 4H). LC-MS: m/z 480.2(M+H)⁺.

Compound 166:5-((1,2,4-thiadiazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(220 mg, 0.5 mmol), 1,2,4-thiadiazol-5-amine (101 mg, 1.0 mmol, 2.0 eq),Pd(OAc)₂ (22 mg, 0.1 mmol, 0.2 eq), Xantphos (57.8 mg, 0.1 mmol, 0.2 eq)and Cs₂CO₃ (325 mg, 1.0 mmol, 2.0 eq) in 1.4-dioxane (10 mL) underheating at 100° C. for 1 hour through microwave irradiation undernitrogen atmosphere. LC-MS: m/z 511.2 (M+H)⁺.

Step F: A solution ofN-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,4-thiadiazol-5-amine(51 mg, 0.1 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30° C.for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 8.23 (s, 1H), 7.77 (d, J=7.0 Hz, 2H), 7.51 (d, J=7.2Hz, 3H), 7.29-7.35 (d, J=8.4 Hz, 2H), 7.01-7.09 (d, J=8.0 Hz, 2H), 5.95(br. s., 1H), 3.83 (s, 3H), 2.24 (br. s., 4H), 1.74 (br. s., 4H). LC-MS:m/z 497.1 (M+H)⁺.

Compound 167:5-((1,3,4-thiadiazol-2-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(446 mg, 1.0 mmol), 1,3,4-thiadiazol-2-amine (101 mg, 1.0 mmol, 1 eq)and Pd(OAc)₂ (91.5 mg, 0.1 mmol, 0.1 eq), xant-phos (115.6 mg, 0.2 mmol,0.2 eq) and Na₂CO₃ (212 mg, 2.0 mmol, 2.0 eq) in toluene (40 mL) underheating at 110° C. for 5 hour under nitrogen atmosphere. LC-MS: m/z511.2 (M+H)⁺.

Step F: A mixture ofN-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,4-thiadiazol-2-aminein(102 mg, 0.2 mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at roomtemperature overnight. The mixture was concentrated in vacuo. Theresidue was basified with saturated sodium hydrogen carbonate solutionto afford the title compound.

¹H NMR (DMSO-d₆): δ 13.77 (br. s., 0.5H), 10.56 (br. s., 0.5H), 9.09(br. s., 1H), 7.74 (d, J=7.02 Hz, 2H), 7.40-7.57 (m, 3H), 7.31 (m,J=8.24 Hz, 2H), 7.05 (m, J=8.55 Hz, 2H), 6.03 (br. s., 1H), 3.83 (s,3H), 2.29 (br. s., 2H), 2.08 (br. s., 2H), 1.70 (br. s., 4H). LC-MS: m/z497.1 (M+H)⁺.

The following compounds were prepared according to the procedure forpreparing compound 101, steps E-F, starting from6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline.

Compound 168:2,3-diphenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(250 mg, 0.541 mmol), pyridin-2-amine (102 mg, 1.08 mmol), palladium(II)acetate (121 mg, 0.541 mmol), xantphos (296 mg, 0.541 mmol) and cesiumcarbonate (354 mg, 1.08 mmol) in 1,4-dioxane (10 mL) was stirred undernitrogen atmosphere in a sealed tube and heated to 110° C. undermicrowave for 1 hour to afford2,3-diphenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 15.93 (br. s., 1H), 9.36 (s, 1H), 8.74 (d, J=8.06Hz, 1H), 8.16-8.34 (m, 2H), 8.07 (d, J=3.76 Hz, 1H), 7.99 (d, J=8.33 Hz,1H), 7.75-7.85 (m, 2H), 7.60 (t, J=7.52 Hz, 4H), 7.39-7.54 (m, 5H),7.21-7.28 (m, 1H), 7.09-7.17 (m, 1H), 6.98 (s, 1H). LC-MS: m/z 507.2(M+H)⁺.

Compound 169:2,3-diphenyl-5-(pyrimidin-4-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(600 mg, 1.3 mmol), pyrimidin-4-amine (148 mg, 1.56 mmol, 1.2 eq),Pd(OAc)₂ (43.7 mg, 0.19 mmol, 0.15 eq), Xantphos (112 mg, 0.19 mmol,0.15 eq) and Cs₂CO₃ (844 mg, 2.6 mmol, 2.0 eq) in 1.4-dioxane (15 mL)under heating at 110° C. through microwave irradiation for 1 hour undernitrogen atmosphere. LC-MS: m/z 521.9 (M+H)⁺.

Step F: A solution of7-methoxy-2,3-diphenyl-N-(pyrimidin-4-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-amine(271 mg, 0.52 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 14.65 (s, 1H), 9.64 (s, 1H), 8.92 (s, 1H), 8.43 (m,4H), 8.12-7.96 (m, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.55 (m, 3H), 7.50 (d,J=6.8 Hz, 2H), 7.37 (s, 4H), 7.19 (s, 1H). LC-MS: m/z 507.9 (M+H)⁺.

Compound 170:5-(isoxazol-3-ylamino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(100 mg, 0.216 mmol), isoxazol-3-amine (92 mg, 0.432 mmol),palladium(II) acetate (53 mg, 0.238 mmol), xantphos (150 mg, 0.259 mmol)and sodium carbonate (51 mg, 0.475 mmol) in 1,4-dioxane (10 mL) underheating at 100° C. through microwave irradiation for 1 hour undernitrogen atmosphere. LC-MS: m/z 511.2 (M+H)⁺.

Step F: A mixture ofN-(7-methoxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine (90 mg, 0.097 mmol) in hydrogen chloride solution (4 Min dioxane, 4 mL) was stirred at room temperature for 10 h. The mixturewas evaporated to dryness. The residue was resolved in dichloromethanesolution (with 10% methanol) and basified with aqueous ammonia to pH 8to afford5-(isoxazol-3-ylamino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 9.39 (d, J=4.03 Hz, 1H), 9.31 (d, J=8.33 Hz, 1H),8.75 (d, J=1.61 Hz, 1H), 8.51 (s, 1H), 8.39 (d, J=8.87 Hz, 1H), 8.25 (d,J=8.87 Hz, 1H), 8.17 (dd, J=8.33, 5.37 Hz, 1H), 7.47-7.58 (m, 4H),7.31-7.46 (m, 6H), 6.44 (bs, 1H). LC-MS: m/z 497.2 (M+H)⁺.

Compound 171: ethyl5-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,3,4-oxadiazole-2-carboxylate

A suspension of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(200 mg, 0.43 mmol), ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (135mg, 0.86 mmol, 2 eq.), Pd(OAc)₂ (20 mg, 0.09 mmol, 0.2 eq.), Xantphos(75 mg, 0.13 mmol, 0.3 eq.) and Cs₂CO₃ (282 mg, 0.87 mmol, 2.0 eq.) in1.4-dioxane (5 mL) was stirred at 100° C. for 16 h under N₂ atmosphere.The mixture was filtered through celite, and the filtrate wasconcentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 12.55 (br. s., 1H), 9.10 (br. s., 1H), 8.85 (br. s.,1H), 8.31 (br. s., 1H), 8.15-8.23 (m, 1H), 8.04-8.15 (m, 1H), 7.84 (br.s., 1H), 7.42-7.60 (m, 4H), 7.38 (d, J=6.2 Hz, 7H), 4.32 (q, J=7.2 Hz,2H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 570.0 (M+H)⁺.

Compound 172:N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide

Step E stoichiometry:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(230 mg, 0.5 mmol) and acetamide (59 mg, 1.0 mmol, 2.0 eq), Pd(OAc)₂ (11mg, 0.05 mmol, 0.1 eq), Xantphos (116 mg, 0.2 mmol, 0.4 eq) and Cs₂CO₃(325 mg, 1.0 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heating at 100°C. through microwave irradiation for 1 hour under nitrogen atmosphere.LC-MS: m/z 586.2 (M+H)⁺.

Step F: A solution ofN-(7-methoxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)acetamide(100 mg, 0.21 mmol) in 4M HCl in 1.4-dioxane (20 mL) was stirred at 30°C. for 5 hours. The reaction mixture was concentrated in vacuo to obtainthe title compound.

¹H NMR (DMSO-d₆): δ 12.96 (br. s., 1H), 10.12 (br. s., 1H), 8.92 (br.s., 1H), 8.40 (br. s., 1H), 8.05 (br. s., 1H), 7.99 (br. s., 1H), 7.76(d, J=8.6 Hz, 1H), 7.42-7.64 (m, 5H), 7.30-7.42 (m, 5H), 1.86-2.03 (m,3H). LC-MS: m/z 472.0 (M+H)⁺.

Compound 173:2-hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide

Step A:2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide

A suspension of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(200 g, 0.43 mmol), 2-(benzyloxy)acetamide (143 mg, 0.86 mmol, 2 eq.),Pd(OAc)₂ (20 mg, 0.09 mmol, 0.2 eq.), Xantphos (75 mg, 0.13 mmol, 0.3eq.) and Cs₂CO₃ (282 mg, 0.86 mmol, 2 eq.) in 1.4-dioxane (5 mL) wasstirred at 100° C. through microwave irradiation for 1 hour under N₂atmosphere. The mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=10/1) to afford the desired product as a yellow solid (120mg).

¹H NMR (DMSO-d₆): δ 12.66 (br. s., 1H), 9.65 (br. s., 1H), 8.91 (br. s.,1H), 8.33 (d, J=8.4 Hz, 1H), 7.96-8.06 (m, 2H), 7.74-7.82 (m, 1H),7.44-7.56 (m, 4H), 7.33-7.44 (m, 7H), 7.13-7.23 (m, 3H), 7.01 (d, J=7.3Hz, 2H), 4.32 (s, 2H), 3.97 (s, 2H). LC-MS: m/z 578.0 (M+H)⁺.

Step B:2-hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide

To a solution of2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide(90 mg, 0.156 mmol) in DCM (5 mL) was added BBr₃ (156 mg, 0.623 mmol, 4eq.) at 0° C. The mixture was stirred at r.t. for 2 h. The reaction wasquenched with MeOH at 0° C. to afford the title compound.

¹H NMR (DMSO-d₆): δ 12.67 (br. s., 1H), 10.91 (br. s., 1H), 8.79-8.93(m, 1H), 8.28-8.40 (m, 1H), 7.90-8.09 (m, 2H), 7.73-7.85 (m, 1H),7.26-7.56 (m, 11H), 6.20 (br. s., 1H), 3.85 (br. s., 2H). LC-MS: m/z487.9 (M+H)⁺.

The following compounds were prepared according to the procedure forpreparing compound 101, steps E-F, starting from6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline.

Compound 174:3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:6-(5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline (380 mg, 0.814 mmol), pyridin-2-amine (153 mg, 1.63 mmol),palladium(II) acetate (18 mg, 0.0814 mmol), xantphos (45 mg, 0.0814mmol) and sodium carbonate (173 mg, 1.63 mmol) in 1,4-dioxane (10 mL)under heating at 110° C. for 1 hour through microwave irradiation undernitrogen atmosphere. LC-MS: m/z 525.2 (M+H)⁺.

Step F: A mixture of7-methoxy-2,3-diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-amine(125 mg, 0.238 mmol) in hydrogen chloride solution (4 M in dioxane, 5mL) was stirred at room temperature for 16 h. The mixture was evaporatedto dryness. The residue was resolved in dichloromethane solution (with10% methanol) and washed with aqueous sodium bicarbonate to pH 8. Theorganic phase was dried over sodium sulfate to afford3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]-pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 15.37 (br. s., 1H), 9.35 (s, 1H), 9.18 (br. s., 1H),8.87 (d, J=8.24 Hz, 1H), 8.18-8.36 (m, 3H), 8.04 (d, J=8.55 Hz, 1H),7.88 (dd, J=7.93, 4.88 Hz, 1H), 7.81 (t, J=7.02 Hz, 1H), 7.75 (d, J=7.63Hz, 2H), 7.47-7.56 (m, 2H), 7.38-7.46 (m, 1H), 7.22 (d, J=8.54 Hz, 1H),7.10-7.18 (m, 1H), 6.11 (br. s., 1H), 2.38 (br. s., 2H), 2.09 (s, 2H),1.73 (br. s., 4H). LC-MS: m/z 511.2 (M+H)⁺.

Compound 175:3-cyclohexenyl-2-phenyl-5-(pyrazin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:6-(5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline (120 mg, 0.257 mmol), pyrazin-2-amine (50 mg, 0.515 mmol),palladium(II) acetate (11 mg, 0.050 mmol), xantphos (32 mg, 0.055 mmol)and cesium carbonate (171 mg, 0.515 mmol) in 1,4-dioxane (5 mL) underheating at 110° C. for 1 hour through microwave irradiation undernitrogen atmosphere. LC-MS: m/z 526.2 (M+H)⁺.

Step F: A mixture of7-methoxy-2,3-diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-amine(70 mg, 0.133 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL)was stirred at room temperature for 4 h. The mixture was evaporated todryness. The residue was resolved in dichloromethane solution (with 10%methanol) and washed with aqueous sodium bicarbonate to pH 8. Theorganic phase was dried over sodium sulfate to afford2,3-diphenyl-5-(pyrazin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 14.04 (s, 1H), 9.57 (s, 1H), 8.94 (br. s., 1H), 8.55(s, 1H), 8.41 (d, J=7.93 Hz, 1H), 8.24 (s, 1H), 8.26 (s, 1H), 8.04-8.13(m, 2H), 7.81 (d, J=8.54 Hz, 1H), 7.75 (d, J=7.32 Hz, 2H), 7.57 (br. s.,1H), 7.47-7.53 (m, 2H), 7.44 (d, J=7.02 Hz, 2H), 2.36 (br. s., 2H), 2.09(br. s., 2H), 1.72 (br. s., 4H). LC-MS: m/z 512.2 (M+H)⁺.

Compound 176:3-cyclohexenyl-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:6-(5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline (240 mg, 0.510 mmol), isoxazol-3-amine (218 mg, 1.02 mmol),palladium(II) acetate (126 mg, 0.560 mmol), xantphos (354 mg, 0.612mmol) and sodium carbonate (119 mg, 1.12 mmol) in 1,4-dioxane (10 mL)under heating at 100° C. for 16 hours under nitrogen atmosphere. LC-MS:m/z 515.2 (M+H)⁺.

Step F: A mixture ofN-(3-cyclohexenyl-7-methoxy-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine(50 mg, 0.097 mmol) in hydrogen chloride solution (4 M in dioxane, 4 mL)was stirred at room temperature for 2 h. The mixture was evaporated todryness. The residue was resolved in dichloromethane solution (with 10%methanol) and basified with aqueous ammonia to pH 8 to afford3-cyclohexenyl-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 9.39 (d, J=4.30 Hz, 1H), 9.29 (d, J=8.33 Hz, 1H),8.78 (s, 1H), 8.48 (s, 1H), 8.40 (d, J=8.86 Hz, 1H), 8.23 (d, J=8.86 Hz,1H), 8.16 (dd, J=8.19, 5.51 Hz, 1H), 7.75 (d, J=7.25 Hz, 2H) 7.38-7.59(m, 4H), 7.36 (bs, 1H), 6.43 (s, 1H), 6.06 (bs, 1H), 2.30 (bs, 2H), 2.06(bs, 2H), 1.70 (bs, 2H) 1.23 (bs, 2H). LC-MS: m/z 501.2 (M+H)⁺.

Compound 177:3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:N-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine

The solution of6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline(80 mg, 0.17 mmol), isoxazol-3-amine (43.1 mg, 0.51 mmol), palladiumdiacetate (19.2 mg, 0.09 mmol), Xantphos (59.4 mg, 0.10 mmol) and sodiumcarbonate (54.1 mg, 0.51 mmol) in 1,4-dioxane (8 mL) was refluxed for 12hours under nitrogen atmosphere. After cooling to room temperature, themixture was concentrated to dryness. The residue was purified by flashcolumn (DCM:MeOH=30:1) to obtainN-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine(12 mg) as yellow solid. LC-MS: m/z 516.2 (M+H)⁺.

Step B:3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution ofN-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine(12 mg, 0.02 mmol) in 4M HCl in 1.4-dioxane (2 mL) was stirred at r.t.for 2 hours. The mixture was concentrated, and saturated NaHCO₃(3 mL)was added to obtain3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (TFA-d): δ 8.97 (s, 2H), 8.74 (d, J=1.6 Hz, 1H), 8.14-8.22 (m,2H), 7.91 (dd, J=8.6, 1.9 Hz, 1H), 7.75 (d, J=7.0 Hz, 2H), 7.36-7.54 (m,3H), 6.42 (d, J=1.9 Hz, 1H), 6.07 (br. s., 1H), 2.30 (br. s., 2H), 2.06(d, J=7.0 Hz, 2H), 1.70 (br. s., 4H). LC-MS: m/z 502.2 (M+H)⁺.

Compound 178:3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: 2-(3-chlorophenyl)-3-oxo-3-phenylpropanenitrile

To a solution of 2-(3-chlorophenyl)acetonitrile (6.0 g, 39.58 mmol) inTHF (40 mL) cooled at −78° C. was added NaHMDS (29.7 mL, 59.37 mmol, 2.0M in THF) dropwise. After addition, the mixture was stirred at −78° C.for 1 hour. Then benzoyl chloride (5.5 mL, 47.50 mmol) was addeddropwise. The reaction was slowly warmed to room temperature and stirredfor 12 hours. The reaction was quenched by saturated NH₄Cl (150 mL),extracted with ethyl acetate (200 mL), washed with water (60 mL) andbrine (60 mL), dried over anhydrous sodium sulfate, and concentrated toobtain crude product (16 g) which was directly used in the next stepwithout further purification.

Step B: 4-(3-chlorophenyl)-3-phenyl-1H-pyrazol-5-amine

The solution of 2-(3-chlorophenyl)-3-oxo-3-phenylpropanenitrile (16 g,crude) and NH₂NH₂ (11.5 mL, 237.48 mmol) in EtOH/AcOH (80 mL/20 mL) wasstirred at 80° C. for 6 hours. After cooling to room temperature, themixture was concentrated by vacuum. The residue was diluted with EtOAc(200 mL), washed with saturated NaHCO₃(100 mL) and brine (50 mL), driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash column (petroleum ether/ethyl acetate=3:1) to obtain4-(3-chlorophenyl)-3-phenyl-1H-pyrazol-5-amine (1.6 g) as a yellowsolid.

¹H NMR (CHLOROFORM-d): δ 7.79-7.85 (m, 3H), 7.51-7.56 (m, 1H), 7.42-7.48(m, 3H), 7.29-7.36 (m, 2H). LC-MS: m/z 270.1 (M+H)⁺.

Step C:3-(3-chlorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The suspension of 4-(3-chlorophenyl)-3-phenyl-1H-pyrazol-5-amine (1.6 g,5.93 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (1.7 g, 7.12 mmol)in xylene (30 mL) was stirred at 150° C. for 12 hours. After cooling toroom temperature, the mixture was filtered and washed with MeOH (2 mL)to obtain3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(830 mg) as a white solid. LC-MS: m/z 444.1 (M+H)⁺.

Step D:5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

The solution of3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(800 mg, 1.80 mmol), N,N-dimethylaniline (436.8 mg, 3.60 mmol) andpentachlorophosphorane (375.3 mg, 1.80 mmol) in POCl₃(8 mL) in a sealedtube was stirred at 100° C. for 8 hours. After cooling to roomtemperature, the solvent was removed by vacuum. The residue was cooledto 0° C. and basified by adding MeOH (6 mL). The precipitate wasfiltered to obtain5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(700 mg) as a yellow solid. LC-MS: m/z 480.1 (M+H)⁺.

Step E:5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

To the solution of5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(700 mg, 1.46 mmol) in DCM/MeOH (20 mL, 1:1) cooled at 0° C. was addedsodium methanolate (0.9 mL, 5.0 M in methanol) dropwise. Then themixture was stirred at 0° C. for 15 minutes. Saturated NH₄Cl (50 mL) wasadded to quench the reaction. The mixture was extracted with DCM (100mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by flash column (petroleumether/ethyl acetate/DCM=20:1:1) to obtain5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(520 mg) as a yellow solid.

¹H NMR (CHLOROFORM-d): δ 7.64-7.68 (m, 2H), 7.56-7.59 (m, 1H), 7.39-7.45(m, 4H), 7.34-7.37 (m, 2H), 7.30-7.33 (m, 2H), 7.03-7.08 (m, 2H), 4.16(s, 3H), 3.92 (s, 3H). LC-MS: m/z 476.1 (M+H)⁺.

Step F:3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

The mixture of5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo-[1,5-a]pyrimidine(120 mg, 0.25 mmol), pyridin-2-amine (47.4 mg, 0.50 mmol), palladiumdiacetate (28.3 mg, 0.13 mmol), Xantphos (72.9 mg, 0.13 mmol) and cesiumcarbonate (123.1 mg, 0.38 mmol) in 1,4-dioxane (6 mL) was reacted inmicrowave reactor at 120° C. for 1.5 hours under nitrogen atmosphere.After cooling to room temperature, the mixture was filtered with celite,diluted with DCM (100 mL), washed with saturated brine (30 mL), driedover anhydrous sodium sulfate and concentrated to dryness. The residuewas purified by flash column (petroleum ether/ethyl acetate/DCM/=6:1:1)to obtain3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(78 mg) as a yellow solid. LC-MS: m/z 534.2 (M+H)⁺.

Step G:3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(70 mg, 0.13 mmol) in 4M HCl in 1.4-dioxane (6 mL) was stirred at r.t.for 3 hours. The mixture was concentrated, and saturated NaHCO₃(6 mL)was added to obtain3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 15.73 (s, 1H), 9.05 (s, 1H), 8.11 (d, J=3.8 Hz, 1H),7.81 (t, J=8.1 Hz, 1H), 7.53-7.60 (m, 4H), 7.40-7.50 (m, 4H), 7.30-7.38(m, 4H), 7.09-7.15 (m, 1H), 7.07 (d, J=8.6 Hz, 2H), 3.85 (s, 3H). LC-MS:m/z 520.3 (M+H)⁺.

Compound 179:3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile

To a solution of 2-(2-fluorophenyl)acetonitrile (5.4 g, 40 mmol) inanhydrous THF (50 mL) was added dropwise of LDA (26 mL, 52 mmol, 1.3 eq)at −78° C. After addition, the mixture was stirred at −78° C. for 0.5 h.Then methyl benzoate (6.0 g, 44 mmol, 1.1 eq) in THF (10 mL) was addedslowly and stirred at RT overnight. The suspension was quenched withNH₄Cl solution (30 mL) and extracted with EA. The organic phase waswashed with water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile (12 g, crude) which wasused directly to the next step without further purification. LC-MS: m/z240.1 (M+H)⁺.

Step B: 4-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-amine

To a solution of 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile (12 g,40 mmol) in EtOH (80 mL) and AcOH (20 mL) was added hydrazine hydrate(4.48 g, 80 mmol, 2.0 eq). Then the reaction mixture was stirred atreflux for 4 h. The solvents were removed in vacuo, and the residue wasadjusted to 8-9 with saturated sodium bicarbonate solution. The mixturewas extracted with EtOAc, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (EtOAc/PE=1/1) to afford the desiredproduct (1.3 g). LC-MS: m/z 254.1 (M+H)⁺.

Step C:3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The dimethyl 2-(4-methoxyphenyl)malonate (886 mg, 3.7 mol, 1.2 eq),4-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-amine (780 mg, 3.1 mol, 1.0 eq)and xylene (15 mL) were added into the 100 mL bottle and heated to 15°C. for 8 h. The reaction mixture was then cooled to room temperature.The mixture was filtered off, and the filter cake was washed with PE toafford the desired product3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(1 g) as a white solid. LC-MS: m/z 427.9 (M+H)⁺.

Step D:5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

A solution of3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(1.0 g, 2.3 mmol) in phosphorus oxychloride (10 mL) was heated to refluxovernight. The mixture was concentrated under reduced pressure. Theresidue was added slowly into MeOH (10 mL) and filtered. The filter cakewas washed with MeOH to afford the desired product5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(890 mg) as a white solid. LC-MS: m/z 464.1 (M+H)⁺.

Step E:5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(463 mg, 1 mmol) in DCM (10 mL) and MeOH (10 mL) cooled at 0° C. wasadded dropwise the sodium methoxide (1 mL, 5 mol, 30% in MeOH). Then thereaction mixture was stirred at 0° C. for 0.5 h. The suspension wasquenched with NH₄Cl solution (30 mL) and extracted with EA. The combinedorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (EtOAc/PE=1/5) toafford the desired product.5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(390 mg). LC-MS: m/z 460.1 (M+H)⁺.

Step F:3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(230 mg, 0.5 mmol), pyridin-2-amine (94 mg, 1 mmol, 2.0 eq), Pd(OAc)₂(22 mg, 0.1 mmol, 20 mol %), Xantphos (115 mg, 0.2 mmol, 40 mol %) andCs₂CO₃ (325 mg, 1 mmol, 2.0 eq) in 1.4-dioxane (10 mL) in a 10 mLmicrowave vial was heated at 100° C. under microwave irradiation for 1 hunder N₂ atmosphere. The reaction was then cooled and filtered. The darkfiltrate was concentrated in vacuo. The residue was purified by columnchromatography on silica gel (EtOAc/PE=1/4) to afford the desiredproduct3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(100 mg). LC-MS: m/z 518.2 (M+H)⁺.

Step G:3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(85 mg, 0.16 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30°C. for 18 hours. The reaction mixture was concentrated in vacuo toafford the title compound.

¹H NMR (DMSO-d₆): δ 8.04 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.49-7.59 (m,3H), 7.31-7.45 (m, 9H), 7.11 (t, J=6.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H),3.82 (s, 3H). LC-MS: m/z 504.0 (M+H)⁺.

Compound 180:6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile

To a solution of methyl picolinate (20 g, 0.15 mol) and2-phenylacetonitrile (20 g, 0.18 mol) in THF (200 mL) was added slowlyNaHDMS (80 mL, 2 mmol/mL) at 0° C. Then the reaction mixture was stirredfor 1 h at 0° C. and allowed to room temperature overnight. The mixturewas poured into water and extracted with ethyl acetate (100 mL*3). Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile (crude, 25 g). LC-MS: m/z223.3 (M+H)⁺.

Step B: 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine

To a solution of 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile (25 g,0.126 mol) in EtOH (200 mL) was added AcOH (20 mL). The reaction mixturewas heated to 60° C. for 10 minutes, and then hydrazine monohydrate (7g, 0.138 mol) was added dropwise via a syringe. Then the reactionmixture was stirred for 4 h at 60° C. The mixture was concentrated todryness. The residue was poured into water and extracted with ethylacetate (100 mL*3). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to give the crude product. The crudeproduct was purified by column chromatography on silica gel (elutingPE/EA=2:1) to give 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3 g).LC-MS: m/z 237.2 (M+H)⁺.

Step C:6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

A solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.5 g, 6.35mmol) and dimethyl 2-(4-methoxyphenyl)malonate (1.67 g, 7.0 mmol) intoluene (50 mL) was heated to 140° C. overnight. The reaction mixturewas cooled to room temperature. The precipitate was filtered off to give6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(1.2 g). LC-MS: m/z 411.2 (M+H)⁺.

Step D:5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

A solution of6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(1 g, 2.44 mmol) in POCl₃ (15 mL) in a sealed tube was heated to 120° C.overnight. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was adjusted to PH=7 by addingsaturated NaHCO₃ solution, extracted with ethyl acetate (50 mL*3),filtered, and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel (eluting PE/EA=10:1) to give5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(900 mg). LC-MS: m/z 447.3 (M+H)⁺.

Step E:5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(900 mg, 2.0 mmol) in MeOH (50 mL) was added NaOMe (0.5 mL, 5.0 mmol/mL)at 0° C. The reaction mixture was stirred for 30 mins. The mixture wasadjusted to PH=7 by adding 1N HCl solution. Then the mixture was pouredinto water and extracted with ethyl acetate, dried over anhydrousNa₂SO₄, filtered, and concentrated. The resultant solid was washed withethyl acetate to give the desired product5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(500 mg). LC-MS: m/z 443.4 (M+H)⁺.

Step F:7-methoxy-6-(4-methoxyphenyl)-3-phenyl-N,2-di(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(150 mg, 0.34 mmol), pyridin-2-amine (35 mg, 0.37 mmol), Pd(OAc)₂ (7.6mg, 0.034 mmol), xantphos (40 mg, 0.068 mmol), and Cs₂CO₃ (222 mg) indioxane (5 mL) was heated to 120° C. for 2 h under N₂. The mixture wascooled to room temperature and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (eluting DCM/MeOH=20:1)to give the desired product (crude, 80 mg), which was used directly tothe next step without further purification.

Step G:6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of7-methoxy-6-(4-methoxyphenyl)-3-phenyl-N,2-di(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(crude 80 mg) in MeOH (5 mL) was added HCl in dioxane (5 mL, 4 mmol/mL).The reaction mixture was stirred for 30 mins. The reaction mixture wasconcentrated in vacuo. The residue was basified with saturated NaHCO₃ togive the desired product6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 15.86 (s, 1H), 9.05 (s, 1H), 8.52 (d, J=4.8 Hz, 1H),7.98-8.10 (m, 1H), 7.92 (d, J=3.8 Hz, 2H), 7.80 (s, 1H), 7.45-7.60 (m,4H), 7.27-7.45 (m, 5H), 7.00-7.14 (m, 3H), 3.84 (s, 3H). LC-MS: m/z487.2 (M+H)⁺.

Compound 181:6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (2 g,8.254 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (2.95 g, 12.38mmol) in tributylamine (25 mL) was warmed up to 180° C. for 2.5 hoursunder N₂ protection. The mixture was cooled to the room temperature andstirred with petroleum ether. The precipitates was filtered and washedwith EtOAc to afford5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(3 g) as a yellow solid. LC-MS: m/z 417.2 (M+H)⁺.

Step B:5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine

The solution of5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(3 g, 7.203 mmol) in POCl₃ (30 mL) was warmed up to 100° C. overnight.The reaction mixture was concentrated to remove POCl₃. The residue wasbasified with saturated sodium hydrogen carbonate solution at 0° C., andextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to afford crude product (2.5 g) as a yellow solid.LC-MS: m/z 453.1 (M+H)⁺.

Step C:5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine(1 g, 2.4 mmol) in methanol (20 mL) was added MeONa (30% wt in methanol,1.3 mL, 7.2 mmol) at 0° C. and stirred at 0° C. for 3 hours. Thereaction was quenched with ice water at 0° C., diluted with saturatedsodium hydrogen carbonate solution at 0° C., and extracted with EtOAc(2×20 mL). The combined organic layers were washed with brine (30 mL),dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column (DCM:MeOH=30:1) to afford5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine(550 mg) as a yellow solid. LC-MS: m/z 449.2 (M+H)⁺.

Step D:7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine(200 mg, 0.446 mmol), pyridin-2-amine (125 mg, 12.38 mmol, 3 eq),Pd(OAc)₂ (20 mg, 0.089 mmol, 0.2 eq), Xant-phos (103 mg, 0.178 mmol, 0.4eq) and Na₂CO₃ (188 mg, 1.782 mmol, 4 eq) in 1,4-dioxane (5 mL) wasstirred and warmed up to 100° C. through microwave irradiation for 1hour under N₂ atmosphere. The reaction was cooled to room temperature,diluted with saturated sodium hydrogen carbonate solution, and extractedwith EtOAc (2×30 mL). The combined organic layers were washed with brine(20 mL), dried over anhydrous sodium sulfate, and concentrated invacuo.The residue was purified by pre-TLC (eluting DCM/MeOH=20:1) to obtain7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(80 mg) as a white solid.

¹H NMR (DMSO-d₆) δ 8.49 (d, J=5.64 Hz, 1H), 8.21-8.38 (m, 2H), 8.07 (d,J=7.25 Hz, 2H), 7.36-7.60 (m, 6H), 7.16 (d, J=8.60 Hz, 2H), 4.13 (s,3H), 3.86 (s, 3H), 3.51 (br. s., 4H), 1.80 (br. s., 4H), 1.60 (br. s.,2H). LC-MS: m/z 507.2 (M+H)⁺.

Step E:6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(100 mg, 0.198 mmol) in 4.0M HCl in 1.4-dioxane (10 mL) was stirred atroom temperature for 2 hours. The reaction mixture was concentrate invacuo. The residue was dissolved in 7N NH₃ in methanol and concentratedin vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 8.31 (d, J=4.88 Hz, 1H), 8.12 (d, J=7.63 Hz, 2H),7.94 (t, J=7.32 Hz, 1H), 7.41-7.53 (m, 4H), 7.34 (m, J=8.55 Hz, 2H),7.19 (t, J=6.26 Hz, 1H), 7.03 (m, J=8.55 Hz, 2H), 3.82 (s, 3H), 3.20(br. s., 4H), 1.73 (br. s., 4H), 1.53-1.68 (m, 2H). LC-MS: m/z 493.4(M+H)⁺.

Compound 182:5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(500 mg, 1.1 mmol) and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (314 mg, 1.47mmol) and Pd(OAc)₂ (38 mg, 0.16 mmol), Xantphos (98 mg, 0.16 mmol) andCs₂CO₃ (740 mg, 2.2 mmol) in 1.4-dioxane (10 mL) was stirred and heatedto reflux for 16 hours under N₂ atmosphere. The reaction was monitoredby LC-MS until the complete conversion of the starting material. Thereaction was then cooled to r.t. and filtered. The dark filtrate wasconcentrated in vacuo and purified by flash column chromatographyeluting with DCM:MeOH=40:1 to obtain the Intermediate 2 (500 mg) as awhite solid. LC-MS: m/z 619.5 (M+H)⁺.

Step B:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

The Intermediate 2 (500 mg, 0.81 mmol) and sodium 2-methylpropan-2-olate(155 mg, 1.62 mmol) in dioxane was stirred at 110° C. for 1 h under MW.The mixture was acidified to PH=7 and concentrated to give the crudeproduct which was directly used to the next step without furtherpurification. LC-MS: m/z 605.3 (M+H)⁺.

Step C:5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The Intermediate 3 (300 mg, 0.49 mmol) in DCM (5 mL) and TFA (5 mL) wasstirred at 60° C. for 1 h. Then the mixture was concentrated to give thecrude product which was added into ammonia water (5 mL) and stirred onfor 1 h. The mixture was concentrated to give the desired product.

1H NMR (DMSO-d₆): δ 13.46 (s, 1H), 12.67 (br. s., 1H), 8.96 (br. s.,1H), 7.70 (br. s., 1H), 7.47-7.58 (m, 4H), 7.35-7.43 (m, 6H), 7.29 (s,1H), 7.06 (d, J=8.6 Hz, 2H), 6.00-6.09 (m, 1H), 3.84 (s, 3H). LC-MS: m/z475.5 (M+H)⁺.

Compound 183:5-((5-methoxy-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to the procedure for preparingcompound 182 by using Intermediate 5 as5-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-3-amine in step A.

Step A: A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(441 mg, 1 mmol),5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (243mg, 1 mmol, 1 eq.), Pd(OAc)₂ (44.8 mg, 0.2 mmol, 0.2 eq.), Xantphos(57.8 mg, 0.1 mmol, 0.1 eq.) and Cs₂CO₃ (650 mg, 2 mmol, 2 eq.) in1.4-dioxane (5 mL) was stirred at 110° C. for 16 hour under N₂atmosphere. The mixture was filtered through celite, and the filtratewas concentrated in vacuo. The crude product was directly used in thenext step without further purification. LC-MS: m/z 649.4 (M+H)⁺

Step B: A mixture of7-methoxy-N-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(800 mg, 1.23 mmol) and sodium 2-methylpropan-2-olate (197 mg, 4.9 mmol)in dioxane (10 mL) was stirred at 100° C. for 2 h. The mixture wasacidified to PH=7 and concentrated to give the crude product which waspurified by silica gel chromatography (DCM:MeOH=40:1) to afford5-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(300 mg) as gray solid. LC-MS: m/z 635.3 (M+H)⁺.

Step C: A solution of5-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.19 mmol) in 4M HCl in dioxane (5 mL) was stirred at r.t. for1 hour. Solvent and volatile were removed in vacuo. The residue wasdissolved in DCM (5 mL) and treated with saturated NaHCO₃. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄,and concentrated in vacuo to afford the title compound.

¹H NMR (CHLOROFORM-d): δ 7.49-7.66 (m, 3H), 7.45 (br. s., 3H), 7.37 (br.s., 4H), 7.31 (br. s., 4H), 7.06 (br. s., 2H), 5.27 (br. s., 1H), 3.84(s, 3H), 3.87 (s, 3H). LC-MS: m/z 505.5 (M+H)⁺.

Compound 184:5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:6-(4-methoxyphenyl)-2,3-diphenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(300 mg, 0.68 mmol),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-amine (289.7 mg, 1.36mmol), palladium diacetate (30.5 mg, 0.14 mmol), Xantphos (117.8 mg,0.20 mmol) and cesium carbonate (486.6 mg, 1.49 mmol) in 1,4-dioxane (8mL) was reacted in microwave reactor at 120° C. for 45 minutes undernitrogen atmosphere. After cooling to room temperature, the mixture wasfiltered with celite, diluted with DCM (100 mL), washed with saturatedNH₄Cl (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate andconcentrated to dryness. The residue was purified by pre-TLC(DCM:MeOH=40:1) to obtain7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(110 mg, yellow solid) and6-(4-methoxyphenyl)-2,3-diphenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, yellow solid). LC-MS: m/z 605.3 (M+H)⁺.

Step B:5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To the solution of6-(4-methoxyphenyl)-2,3-diphenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.1 mmol) in DCM (1.5 mL) cooled to 0° C. was added TFA (1.5 mL)dropwise. Then the mixture was stirred at room temperature for 8 h. Themixture was concentrated, and NaOH (1 M) was added to pH>7 to affordpure product.

¹H NMR (TFA-d): δ 8.54 (s, 1H), 7.41-7.67 (m, 11H), 7.37 (d, J=7.3 Hz,2H), 7.22 (d, J=8.6 Hz, 2H), 4.05 (s, 3H). LC-MS: m/z 475.4 (M+H)⁺.

Compound 185:5-((2H-1,2,3-triazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to The procedure for preparingcompound 182 by using Intermediate 5 as2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine in step A.

Step A: A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(50 mg, 0.11 mmol),2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine (31 mg,0.147 mmol, 1.3 eq.), Pd(OAc)₂ (5.1 mg, 0.027 mmol, 0.2 eq.), Xantphos(13.1 mg, 0.027 mmol, 0.2 eq.) and Cs₂CO₃ (66.7 mg, 0.283 mmol, 2.5 eq.)in dioxnae (6 mL) was stirred at 100° C. for 1 hour under N₂ atmospherein microwave. The mixture was filtered through celite, and the filtratewas concentrated in vacuo. The residue was purified by flashchromatography (PE:EA=2/1) to afford7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(30 mg) as a white solid. LC-MS: m/z 619.9 (M+H)⁺.

Step B: A solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(110 mg, 0.18 mmol) and KO^(t)Bu (50 mg, 0.44 mmol) in 1.4-dioxane (5mL) was stirred at reflux for 2 hours. Solvent and volatile were removedin vacuo to afford 6-(4-methoxyphenyl)-2,3-diphenyl-5-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg) which was directly used in the next step without furtherpurification. LC-MS: m/z 605.9 (M+H)⁺.

Step C: A solution of6-(4-methoxyphenyl)-2,3-diphenyl-5-((2-((2-(trimethylsilyl)ethoxy)-methyl)-2H-1,2,3-triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg, 0.21 mmol) in TFA (10 mL) was stirred at r.t. for 1 hours.Solvent and volatile were removed in vacuo. The residue was basifiedwith NH₃.H₂O to pH=8 and concentrated to to afford the title compound.

¹H NMR (DMSO-d₆): δ 7.44-7.62 (m, 5H), 7.24-7.43 (m, 9H), 7.04 (d, J=8.1Hz, 2H), 3.81 (s, 3H). LC-MS: m/z 476.3 (M+H)⁺.

Compound 186:5-((5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]-pyrimidine(300 mg, 0.68 mmol), 1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine (296mg, 1.36 mmol, 2 eq.), Pd(OAc)₂ (30 mg, 0.14 mmol, 0.2 eq.), Xantphos(156 mg, 0.27 mmol, 0.4 eq.) and Cs₂CO₃ (441 mg, 1.36 mmol, 2 eq.) in1.4-dioxane (20 mL) was stirred at 100° C. for 16 hour under N₂atmosphere. The mixture was filtered through celite, and the filtratewas concentrated in vacuo. The residue was purified by flashchromatography (DCM:MeOH=50/1) to affordN3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine(220 mg) as a white solid. LC-MS: m/z 625.5 (M+H)⁺.

Step B:5-((5-amino-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution ofN3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine(160 mg, 0.26 mmol) in MeOH (3 mL) was added 4N NaOH in MeOH (4 mL) andstirred at 80° C. for 2 hours. Solvent and volatile were removed invacuo. The residue was partitioned between water (30 mL) and EA (50 mL).The EA layer was dried and concentrated to give5-((5-amino-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(20 mg) as a white solid. LC-MS: m/z 610.5 (M+H)⁺.

Step C:5-((5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a5-((5-amino-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(20 mg, 0.03 mmol) in TFA (2 mL) was added Tf₂O (0.5 mL). The resultantmixture was stirred at rt for 4 h. Then the mixture was concentratedbelow 40° C. to give the title compound.

¹H NMR (DMSO-d₆): δ 13.94 (br. s., 1H), 11.27 (br. s., 1H), 8.67 (s,1H), 7.44-7.56 (m, 4H), 7.31-7.40 (m, 6H), 7.21-7.30 (m, J=8.3 Hz, 2H),6.95-7.06 (m, J=8.6 Hz, 2H), 5.25 (br. s., 2H), 5.13 (s, 1H), 3.82 (s,3H). LC-MS: m/z 490.1 (M+H)⁺.

Compound 187:5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(300 mg, 0.65 mmol),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (166 mg, 0.78mmol, 1.2 eq.), Pd(OAc)₂ (30 mg, 0.13 mmol, 0.2 eq.), Xantphos (28 mg,0.13 mmol, 0.2 eq.) and K₂CO₃ (147 g, 1.30 mmol, 2.0 eq.) in dioxnae (10mL) was stirred at 90° C. for 4 hour. The mixture was filtered throughcelite, and the filtrate was concentrated in vacuo. The residue waspurified by flash chromatography (PE/EA/DCM=10/1/1) to afford2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg) as a white solid. LC-MS: m/z625.9 (M+H)⁺.

Step B:5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg, 0.14 mmol) in TFA (8 mL) wasstirred at rt for 1 hour. Solvent and volatile were removed in vacuo.The mixture was basified with ammonia to pH=8 and concentrated to givethe crude product to afford the title compound.

¹H NMR (TFA-d): δ 9.32 (br. s., 1H), 9.25 (br. s., 1H), 8.66 (br. s.,1H), 8.57 (d, J=8.3 Hz, 1H), 8.43 (br. s., 1H), 8.25 (br. s., 1H), 7.80(br. s., 2H), 7.64 (s, 3H), 7.68 (s, 2H), 7.57 (br. s., 4H), 6.27 (br.s., 1H). LC-MS: m/z 496.2 (M+H)⁺.

Compound 188:5-((5-methyl-1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to the procedure for preparingcompound 182 by using Intermediate 1 as6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolineand Intermediate 5 as5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine in stepA.

Step E stoichiometry:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(200 mg, 0.432 mmol),5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (147mg, 0.65 mmol), Pd(OAc)₂ (10 mg, 0.043 mmol), xantphos (50 mg, 0.086mmol), Cs₂CO₃ (281 mg, 0.86 mmo) in dioxane (15 mL) under heating to110° C. overnight under N₂. LC-MS: m/z 640.3 (M+H)⁺.

Step F: To a solution of5-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.63 mmol) in DCM (90 mL) was added TFA (3 mL). The reactionmixture was stirred for 30 mins at room temperature. The mixture wasconcentrated in vacuo. The residue was basified with ammonia (4 mL) andconcentrated to to give the desired product.

¹H NMR (DMSO-d₆): δ 13.65 (br. s., 1H), 12.35 (br. s., 1H), 9.15 (br.s., 1H), 8.94 (d, J=3.0 Hz, 1H), 8.42 (d, J=8.3 Hz, 1H), 8.10 (d, J=8.6Hz, 1H), 8.02 (s, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.48-7.59 (m, 4H),7.26-7.47 (m, 5H), 5.74 (s, 1H), 2.18 (s, 3H). LC-MS: m/z 509.9 (M+H)⁺.

Compound 189:5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(300 mg, 0.67 mmol),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (430.8 mg, 2.02mmol), palladium diacetate (30.2 mg, 0.13 mmol), Xantphos (116.8 mg,0.20 mmol) and cesium carbonate (438.4 mg, 1.35 mmol) in 1,4-dioxane (6mL) was reacted in microwave reactor at 100° C. under N₂ atmosphere for45 minutes. After cooling to room temperature, the reaction mixture wasdiluted with DCM (100 mL), filtered with celite, washed with aqueousNH₄Cl (30 mL) and saturated brine (30 mL), dried over anhydrous sodiumsulfate, and concentrated. The residue was purified by flash column(petroleum ether/ethyl acetate=4:1) to obtain3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(220 mg) as a yellow solid. LC-MS: m/z 623.3 (M+H)⁺.

Step B:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(220 mg, 0.35 mmol), sodium tert-butoxide (67.9 mg, 0.71 mmol) and water(3 drops) in 1,4-dioxane (8 mL) was reacted in microwave reactor at 100°C. for 1.5 hours. After cooling to room temperature, the mixture wasdiluted with DCM (100 mL), washed with water (25 mL) and brine (25 mL),dried over anhydrous sodium sulfate and concentrated. MeOH (4 mL) wasadded to the residue, and the precipitate was filtered, washed with MeOH(4 mL) to obtain3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg) as a yellow solid. LC-MS: m/z 609.3 (M+H)⁺.

Step C:5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg, 0.21 mmol) in TFA/DCM (2 mL/1 mL) was stirred at roomtemperature for 4 hours to obtain5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.30 (s, 1H), 12.77 (br. s., 1H), 8.90 (s, 1H),7.72 (d, J=7.3 Hz, 2H), 7.44-7.53 (m, 2H), 7.37-7.44 (m, 1H), 7.28 (d,J=8.6 Hz, 2H), 7.14 (s, 0.5H), 6.97-7.08 (m, 2.5H), 6.09 (s, 1H), 6.01(br. s., 1H), 3.80-3.88 (m, 3H), 2.38 (br. s., 2H), 2.04 (br. s., 2H),1.61-1.83 (m, 4H). LC-MS: m/z 479.1 (M+H)⁺.

Compound 190:5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(350 m g, 0.8 mmol) and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (356.4 mg, 1.7mmol) and Pd(OAc)₂ (206.3 mg, 0.9 mmol), Xantphos (579.9 mg, 1.0 mmol)and Cs₂CO₃ (597.7 m g, 1.8 mmol) in 1.4-dioxane (8 mL) was stirred andheated to reflux for 12 hours under N₂ atmosphere. The reaction was thencooled to r.t. and filtered with celite, diluted with DCM (60 mL),washed with saturated ammonium chloride (30 mL) and brine (30 mL), driedover anhydrous sodium sulfate and concentrated to dryness. The residuewas purified by flash column (DCM:MeOH=25:1) to obtain3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(160 mg) as a brown solid. LC-MS: m/z 630.3 (M+H)⁺.

Step B:5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To the solution of3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(60 mg, 0.1 mmol) in DCM (1 mL) cooled to 0° C. was added TFA (2 mL)dropwise. The mixture was then stirred at room temperature for 2 h. Themixture was concentrated, and NH₄OH (5 mL) was added to obtain5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.37 (br. s., 1H), 9.13 (br. s., 1H), 8.88-8.98 (m,1H), 8.41 (d, J=8.1 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 8.00 (s, 1H),7.67-7.82 (m, 4H), 7.33-7.63 (m, 5H), 6.02 (br. s., 2H), 2.38 (br. s.,2H), 2.09 (br. s., 2H), 1.72 (br. s., 4H). LC-MS: m/z 500.2 (M+H)⁺.

Compound 191:3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline(150 mg, 0.32 mmol),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (137.0 mg, 0.65mmol), palladium diacetate (14.5 mg, 0.05 mmol), Xantphos (55.5 mg, 0.10mmol) and cesium carbonate (209.5 mg, 0.65 mmol) in 1,4-dioxane (6 mL)was reacted in microwave reactor at 100° C. under N₂ atmosphere for 45minutes. After cooling to room temperature, the reaction mixture wasdiluted with DCM (100 mL), filtered with celite, washed with aqueousNH₄Cl (30 mL) and saturated brine (30 mL), dried over anhydrous sodiumsulfate and concentrated. The residue was purified by prep-TLC(DCM/MeOH=30:1) to obtain3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(80 mg) as a brown solid. LC-MS: m/z 645.3 (M+H)⁺.

Step B:3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(80 mg, 0.1 mmol) and ^(t)BuOK (83.5 mg, 0.7 mmol) in dioxane/H₂O (6mL/1 mL) was stirred at 100° C. for 8 h. After cooling to roomtemperature, the mixture was diluted with DCM (60 mL), washed with water(30 mL) and brine (20 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by prep-TLC (DCM:MeOH=15:1) to affordyellow solid (50 mg). LC-MS: m/z 631.3 (M+H)⁺.

Step C:5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To the solution of3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.05 mmol) in DCM (1.5 mL) cooled to 0° C. was added TFA (1.5mL) dropwise. The mixture was then stirred at room temperature for 2 h.The mixture was concentrated, and NH₄OH (5 mL) was added to obtain5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.38 (br. s., 1H), 12.83 (br. s., 1H), 9.29 (br.s., 1H), 8.97 (s, 2H), 8.17 (d, J=8.5 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H),7.89 (d, J=8.5 Hz, 1H), 7.74 (d, J=7.0 Hz, 3H), 7.45-7.52 (m, 2H),7.37-7.44 (m, 1H), 6.04 (br. s., 1H), 5.97 (br. s., 1H), 2.39 (br. s.,2H), 2.03-2.11 (m, 2H), 1.72 (d, J=4.0 Hz, 5H). LC-MS: m/z 501.2 (M+H)⁺.

Compound 192:6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine

A suspension of Intermediate 1 (880 mg, 2 mmol), NH₃/dioxane (0.4N, 15mL, 6.0 mmol, 3 eq) and tBuBrettphos Pd G3 (540 mg, 0.4 mmol, 0.2 eq),tBuBrettphos (98 mg, 0.2 mmol, 0.1 eq), t-BuONa (580 mg, 6 mmol, 3.0 eq)and 1.4-dioxane (4 mL) in a 25 mL microwave vial under N₂ atmosphere.The vial was sealed and heated for 1 h at a constant temperature of 50°C. The reaction was then cooled to r.t. and filtered. The dark filtratewas concentrated in vacuum and purified by flash column chromatographysilica gel (DCM/MeOH=20:1) to obtain the Intermediate 2 (400 mg).

¹H NMR (DMSO-d₆): δ 7.47-7.56 (m, 2H), 7.29-7.43 (m, 10H), 7.19-7.25 (m,1H), 7.08 (d, J=8.8 Hz, 2H), 6.48-5.96 (s, 2H), 4.03 (s, 3H), 3.82 (s,3H). LC-MS: m/z 423.2 (M+H)⁺.

Step B:N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)thiazol-4-amine

A suspension of Intermediate 2 (84 mg, 0.2 mmol), 4-bromothiazole (164mg, 1.0 mmol, 5 eq), tBuBrettphos Pd G3 (54 mg, 0.04 mmol, 0.2 eq),tBuBrettphos (9.8 mg, 0.02 mmol, 0.1 eq), t-BuONa (58 mg, 0.6 mmol, 3.0eq) and 1.4-dioxane (2 mL) in a 10 mL microwave vial under N₂atmosphere. The vial was sealed and heated for 1 h at a constanttemperature of 80° C. The reaction was then cooled to r.t. and filtered.The dark filtrate was concentrated in vacuum and purified by flashcolumn chromatography silica gel (DCM/MeOH=20:1) to give theIntermediate 3 (40 mg) as a white solid. LC-MS: m/z 406.1 (M+H)⁺.

Step C:6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 3 (40 mg, 0.08 mmol) in HCl/dioxane (5 mL, 1N)was stirred at RT for 1 h. The mixture was then concentrated underreduced pressure to afford the desired product 4.

¹H NMR (DMSO-d₆): δ 9.04 (d, J=2.4 Hz, 1H), 7.48-7.59 (m, 4H), 7.35-7.44(m, 6H), 7.28-7.34 (m, J=8.8 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 7.01-7.09(m, J=9.2 Hz, 2H), 3.83 (s, 3H). LC-MS: m/z 492.1 (M+H)⁺.

Compound 152:5-([1,2,4]triazolo[1,5-c]pyrimidin-7-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to the procedures for preparingcompound 192, step B-C, starting from7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine.

Step B stoichiometry:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-amine(210 mg, 0.5 mmol), 7-chloro-[1,2,4]triazolo[1,5-c]pyrimidine (135 mg,0.9 mmol), Pd(OAc)₂ (62 mg, 0.25 mmol, 0.5 eq.), xantphos (310 mg, 0.5mmol, 1 eq.), and Cs₂CO₃ (500 mg, 1.5 mmol, 3 eq.) in 1,4-dioxane (15mL) under heating at 100° C. through microwave irradiation for 1 hourunder N₂ atmosphere. LC-MS: m/z 541.2 (M+H)⁺.

Step C: The solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine(100 mg, 0.19 mmol) in HCl-1,4-dioxane (15 mL) was stirred at r.t. for 3h. Solvent and volatile were removed in vacuo. The residue was dissolvedin DCM (5 mL) and treated with saturated NaHCO₃. The organic phase wasseparated and washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆): δ 12.73 (br. s., 1H), 9.59 (br. s., 1H), 9.33 (br. s.,1H), 8.47 (s, 1H), 7.43-7.65 (m, 5H), 7.24-7.43 (m, 7H), 7.12 (s, 1H),6.96 (d, J=8.2 Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 527.2 (M+H)⁺.

Compound 193:5-((1H-pyrazol-3-yl)amino)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 182, 50 mg, 0.11 mmol) in anhydrous DCM (5 mL) was added asolution of BBr₃ (40 mg, 0.16 mmol, 1.5 eq) in DCM (0.5 mL) at −78° C.The reaction mixture was stirred at 0° C. for 2 h. The suspension wasquenched with MeOH at −78° C. and extracted with EA. The combinedorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to afford thedesired product5-((1H-pyrazol-3-yl)amino)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.45 (s, 1H), 12.66 (s, 1H), 9.48 (s, 1H), 8.89 (s,1H), 7.70 (s, 1H), 7.51 (d, J=7.2 Hz, 4H), 7.38 (t, J=7.6 Hz, 6H), 7.16(d, J=8.4 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 6.08 (s, 1H). LC-MS: m/z461.7 (M+H)⁺.

Compound 194:3-cyclohexenyl-6-(4-hydroxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 158, 100 mg, 0.204 mmol)and BBr₃ (1M in dichloromethane, 5 mL) was stirred at room temperaturefor 1 h. The mixture was quenched with methanol at 0° C. to afford3-cyclohexenyl-6-(4-hydroxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆): δ 13.87 (s, 1H), 9.52 (s, 1H), 9.28 (s, 1H), 8.62 (s,1H), 8.24 (d, J=2.75 Hz, 1H), 8.20 (s, 1H), 7.73 (d, J=7.02 Hz, 2H),7.39-7.52 (m, 3H), 7.20 (d, J=8.54 Hz, 2H), 6.85 (d, J=8.24 Hz, 2H),6.04 (br. s., 1H), 2.33 (br. s., 2H), 2.04 (br. s., 2H), 1.59-1.77 (m,4H). LC-MS: m/z 477.2 (M+H)⁺.

Compound 195:5-((1H-1,2,4-triazol-3-yl)amino)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Intermediate 1 was prepared according to the procedure for preparingcompound 101 (step A-E) by using Intermediate 9 as1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-amine in step E.LC-MS: m/z 620.3 (M+H)⁺.

Step A: To the solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine1 (80 mg, 0.1 mmol) in DCM (2 mL) cooled to 0° C. was added BBr₃ (1.0 Min DCM, 1.5 mL) dropwise. The mixture was then stirred at 0° C. for 2 h.The reaction was quenched by carefully adding MeOH and concentrated invacuo to give the product.

¹H NMR (DMSO-d₆): δ 14.10 (br. s., 1H), 13.12 (br. s., 1H), 9.51 (br.s., 1H), 9.00 (br. s., 1H), 8.54 (br. s., 1H), 7.46-7.59 (m, 4H),7.29-7.45 (m, 6H), 7.18 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.3 Hz, 2H).LC-MS: m/z 462.3 (M+H)⁺.

Compound 196:6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: dimethyl 2-(2-methylbenzo[d]thiazol-6-yl)malonate

A mixture of 6-bromo-2-methylbenzo[d]thiazole (4.5 g, 19.7 mmol),dimethyl malonate (5.2 g, 39.4 mmol), Pd(OAc)₂ (882 mg, 3.94 mmol),t-BuMePhos (2.45 g, 7.88 mmol), and K₃PO₄ (9.5 g, 45.3 mmol) in 100 mLof anhydrous toluene was stirred at 80° C. under N₂ atmosphere for 16 h.The mixture was filtered and concentrated. The residue was purified bysilica gel column (PE:EA=5:1) to afford Intermediate 2 as white solid(3.6 g).

¹H NMR (CHLOROFORM-d): δ 7.82-8.04 (m, 2H), 7.48 (dd, J=8.3, 1.9 Hz,1H), 4.79 (s, 1H), 3.79 (s, 7H), 2.86 (s, 3H). LC-MS: m/z 280.5 (M+H)⁺.

Step B:5-hydroxy-6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of dimethyl 2-(2-methylbenzo[d]thiazol-6-yl)malonate (3 g,10.7 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (2.1 g, 8.9 mmol) in TEA(20 mL) was stirred at 150° C. for 4 h. The mixture was then cooled tor.t. and filtered. The precipitates were suspended in a mixed solutionof 2 mL THF and 20 mL HCl (1M) and stirred at r.t. for 0.5 h. The solidwas filtered and washed with EA (10 mL) to give the desired product as awhite solid (2.7 g) which was directly used to the next step withoutfurther purification. LC-MS: m/z 451.2 (M+H)⁺.

Step C:6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-methylbenzo[d]thiazole

A mixture of Intermediate 3 (2.7 g, 6 mmol) in POCl₃ (20 mL) was stirredat 120° C. overnight in a sealed tube. The mixture was concentrated. Theresidue was basified with NaHCO₃ solution to PH=7, extracted with DCM(10 mL×3), dried, concentrated and purified by silica gel column(PE:EA=3:1) to give Intermediate 4 (2.1 g) as yellow solid. LC-MS: m/z487.3 (M+H)⁺.

Step D:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-methylbenzo[d]thiazole

The Intermediate 4 (2.1 g, 4.3 mmol) was dissolved in DCM (10 mL) andMeOH (20 mL) at 0° C. NaOMe (464 mg, 8.6 mmol) in MeOH (5 mL) was addeddropwise and stirred on for 16 h at r.t. The mixture was concentrated.The residue was purified by silica gel column (PE:EA=5:1) to give thedesired product 5 (1.6 g) as white solid.

¹H NMR (CHLOROFORM-d): δ 8.07 (d, J=8.2 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H),7.66 (dd, J=7.0, 2.4 Hz, 2H), 7.54 (d, J=7.0 Hz, 2H), 7.48 (dd, J=8.5,1.5 Hz, 1H), 7.35-7.43 (m, 5H), 7.32 (d, J=7.3 Hz, 1H), 4.19 (s, 3H),2.90 (s, 3H). LC-MS: m/z 483.6 (M+H)⁺.

Step E:6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (482 g, 1 mmol), pyrazin-2-amine (94 mg,1 mmol), Pd(OAc)₂ (42.2 mg, 0.2 mmol), Xantphos (23.1 mg, 0.4 mmol) andCs₂CO₃ (652 m g, 2 mmol) in 1.4-dioxane (10 mL) was stirred and heatedto reflux for 16 hours under N₂ atmosphere. The reaction was monitoredby LC-MS until the complete conversion of the starting material. Thereaction mixture was then cooled to r.t. and filtered. The dark filtratewas concentrated in vacuo to obtain the title compound 6.

¹H NMR (CHLOROFORM-d): δ 15.25 (s, 1H), 8.05 (d, J=4.0 Hz, 1H),7.92-8.01 (m, 2H), 7.60-7.70 (m, 4H), 7.45-7.53 (m, 5H), 7.39 (dd,J=6.1, 2.4 Hz, 1H), 7.28 (d, J=4.0 Hz, 3H), 6.97 (dd, J=7.2, 5.0 Hz,2H), 2.71 (s, 3H). LC-MS: m/z 527.5 (M+H)⁺.

Compound 197:6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: 6-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To the mixture of 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (10 g, 47mmol) and K₂CO₃ (13 g, 94 mmol) in DMF (100 mL). was added1-(chloromethyl)-4-methoxybenzene (8.8 g, 56 mmol). The mixture wasstirred at r.t. for 16 h. The mixture was poured into water (30 mL) andextracted with EA (30M1×3). The combined organic layers were dried,concentrated and purified by silica gel column (PE:EA=5:1) to give thedesired product (11 g) as a white solid.

¹H NMR (CHLOROFORM-d): δ 7.12-7.20 (m, J=8.5 Hz, 2H), 6.84-6.90 (m, 2H),6.80 (d, J=2.1 Hz, 1H), 6.61-6.73 (m, 2H), 4.32 (s, 2H), 4.15-4.20 (m,2H), 3.76-3.80 (m, 3H), 3.22-3.30 (m, 2H). LC-MS: m/z 334.5 (M+H)⁺.

Step B: dimethyl2-(4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) malonate

A mixture of Intermediate 2 (5.5 g, 16.5 mmol), dimethyl malonate (2.6g, 19.8 mmol) Pd(OAc)₂ (370 mg, 1.65 mmol), t-BuMePhos (1.96 g, 3.63mmol), and K₃PO₄(8 g, 37.95 mmol) in 30 mL of anhydrous toluene wasstirred at 80° C. under N₂ atmosphere for 16 h. The mixture was filteredand concentrated. The residue was purified by silica gel column(PE:EA=4:1) to afford Intermediate 3 (5.7 g) as a white solid.

¹H NMR (CHLOROFORM-d): δ 7.18-7.24 (m, J=8.9 Hz, 2H), 6.83-6.89 (m,J=8.5 Hz, 2H), 6.73-6.79 (m, 2H), 6.62 (d, J=10.1 Hz, 1H), 4.48 (s, 1H),4.38 (s, 2H), 4.20-4.26 (m, 2H), 3.79 (s, 3H), 3.69 (s, 6H), 3.24-3.31(m, 2H). LC-MS: m/z 386.5 (M+H)⁺.

Step C:5-hydroxy-6-(4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 3 (1.5 g, 3.8 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (760 mg, 3.2 mmol) in TEA (20 mL) wasstirred at 150° C. for 4 h. The mixture was then cooled to r.t. andfiltered. The filter cake was suspended in a mixed solution of 2 mL THFand 20 mL HCl (1M) and stirred at r.t. for 0.5 h. The precipitate wasfiltered and washed with EA (10 mL) to give the product (1.3 g) as awhite solid which was directly used to the next step without furtherpurification. LC-MS: m/z 557.2 (M+H)⁺.

Step D:6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

The Intermediate 4 (1.3 g, 2.3 mmol) was dissolved in POCl₃ (15 mL) andstirred at 120° C. overnight in a sealed tube. The mixture wasconcentrated and basified with NaHCO₃ solution to PH=7. The resultantmixture was extracted with DCM (10 mL×3), dried, and concentrated togive crude Intermediate 5 (2.1 g) as a yellow solid. LC-MS: m/z 473.3(M+H)⁺.

Step E:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

The Intermediate 5 (500 mg, 1.06 mmol) was dissolved in DCM (5 mL) andMeOH (10 mL) at 0° C. NaOMe (114 mg, 2.11 mmol) in MeOH (5 mL) was addeddropwise and stirred on for 16 h at r.t. The mixture was concentratedand purified by silica gel column (PE:EA=6:1) to give the desiredproduct (230 mg) as a white solid.

¹H NMR (CHLOROFORM-d): δ 7.64-7.71 (m, 2H), 7.51-7.59 (m, 2H), 7.36-7.44(m, 5H), 7.32 (d, J=7.3 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.64-6.75 (m,2H), 4.32-4.40 (m, 2H), 4.15-4.19 (m, 3H), 3.48-3.55 (m, 2H). LC-MS: m/z469.4 (M+H)⁺.

Step F:6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-methoxy-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of Intermediate 6 (200 mg, 0.43 mmol), pyrazin-2-amine (48mg, 0.51 mmol), Pd(OAc)₂ (9.6 mg, 0.043 mmol), Xantphos (49.6 mg, 0.086mmol) and Cs₂CO₃ (280 m g, 0.86 mmol) in 1.4-dioxane (10 mL) was heatedto reflux for 16 hours under N₂ atmosphere. The reaction was monitoredby LC-MS until the complete conversion of the starting material. Thereaction mixture was then cooled to r.t. and filtered. The dark filtratewas concentrated in vacuo and purified by flash column chromatographyeluting with DCM:MeOH=40:1 to obtain the Intermediate 7 (120 mg) as awhite solid.

¹H NMR (CHLOROFORM-d): δ 8.79 (d, J=8.5 Hz, 1H), 8.18 (dd, J=4.9, 0.9Hz, 1H), 7.61-7.71 (m, 5H), 7.48 (s, 1H), 7.30-7.44 (m, 6H), 6.89-6.97(m, 2H), 6.63-6.75 (m, 2H), 4.34 (t, J=4.3 Hz, 2H), 4.08-4.11 (m, 3H),3.50 (d, J=4.3 Hz, 2H). LC-MS: m/z 527.2 (M+H)⁺.

Step G:6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of Intermediate 7 (50 m g, 0.095 mmol) in HCl (5 mL, 4M in1.4-dioxane) was stirred at room temperature for 16 h. The mixture wasconcentrated, basified with ammonia (5 mL, 7M in MeOH) and concentratedin vacuo to give the title compound 8.

¹H NMR (DMSO-d₆): δ 15.73 (s, 1H), 8.92 (s, 1H), 8.03 (d, J=4.0 Hz, 1H),7.78 (br. s., 1H), 7.51-7.60 (m, 4H), 7.32-7.47 (m, 7H), 7.09 (d, J=5.8Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.62 (d, J=1.8 Hz, 1H), 6.46-6.54 (m,1H), 5.85 (br. s., 1H), 4.19 (br. s., 2H), 3.34-3.35 (m, 2H). LC-MS: m/z513.5 (M+H)⁺.

Compound 198:6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A:7-methoxy-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-methoxy-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine(50 mg, 0.095 mmol) in THF (10 mL) was cooled to 0° C., HCOOH (5.2 mg,0.114 mmol) was added and stirred for 5 mins. BH₃ THF (0.19 mL, 1M) wasadded dropwise at 0° C., and the mixture was slowly warmed to r.t. andstirred on for 4 h. The reaction was quenched by careful adding NaHCO₃solution. The resultant mixture was extracted with DCM (10 mL×3), dried,and concentrated. The residue was purified by silica gel column(PE:EA=3:1) to afford Intermediate 2 (30 mg) as a light yellow solid.

¹H NMR (CHLOROFORM-d): δ 8.83 (d, J=8.2 Hz, 1H), 8.17 (d, J=4.3 Hz, 1H),7.59-7.73 (m, 5H), 7.35-7.43 (m, 5H), 7.26-7.30 (m, 1H), 6.93 (d, J=7.9Hz, 2H), 6.64-6.75 (m, 2H), 4.39 (t, J=4.1 Hz, 2H), 4.07-4.12 (m, 3H),3.37 (d, J=4.3 Hz, 2H), 2.90 (s, 3H). LC-MS: m/z 541.3 (M+H)⁺.

Step B:6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The Intermediate 2 (30 mg, 0.056 mmol) in HCl (10 mL, 4M in dioxane) wasstirred at r.t. for 2 h. The mixture was concentrated, basified withammonia (5 mL, 7M in MeOH) and concentrated in vacuo to afford the titlecompound 3.

¹H NMR (CHLOROFORM-d): δ 8.07 (d, J=4.6 Hz, 1H), 7.76 (br. s., 2H), 7.65(br. s., 1H), 7.45-7.52 (m, 4H), 7.31-7.41 (m, 5H), 6.98 (br. s., 1H),6.81-6.92 (m, 2H), 6.62-6.76 (m, 2H), 4.37 (br. s., 2H), 3.35 (br. s.,2H), 2.92 (s, 3H). LC-MS: m/z 527.5 (M+H)⁺.

Compound 199:N-ethyl-5-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,3,4-oxadiazole-2-carboxamide

Step A: To a solution of 1 (20 mg, mmol) in THF (2 mL) was addedethylamine (aq. 0.1 mL) in a sealed tube, and the mixture was stirred at50° C. overnight to afford the desired product 2.

¹H NMR (DMSO-d₆): δ 12.67 (br. s., 1H), 8.63-8.92 (m, 2H), 8.28-8.34 (m,2H), 8.03 (s, 1H), 7.92 (s, 2H), 7.49-7.55 (m, 2H), 7.41-7.49 (m, 3H),7.31-7.40 (m, 6H), 3.18 (dt, J=13.2, 7.2 Hz, 2H), 1.04 (t, J=7.2 Hz,3H). LC-MS: m/z 569.0 (M+H)⁺.

Compound 200:(E)-2-hydroxy-1-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)guanidine

Step A:N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)cyanamide

A mixture of Intermediate 1 (441 mg, 1 mmol), NH₂CN (210 mg, 5.0 mmol, 5eq), t-BuBrettphos Pd G3 (170 mg, 0.2 mmol, 0.2 eq), t-BuBrettphos (49mg, 0.1 mmol, 0.1 eq) and t-BuONa (288 mg, 3.0 mmol, 3.0 eq) in1.4-dioxane (12 mL) in a sealed microwave vial (25 mL) under N₂atmosphere was heated to 80° C. for 1 h. The reaction mixture was thencooled to r.t. and filtered. The dark filtrate was concentrated in vacuoand purified by flash column chromatography sillica gel (DCM/MeOH=100:1)to obtain Intermediate 2 (180 mg). LC-MS: m/z 448.1 (M+H)⁺

Step B:(E)-2-hydroxy-1-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)guanidine

To a mixture of Intermediate 2 (100 mg, 0.22 mmol) and DIPEA (145 mg,1.12 mmol, 5.0 eq) in EtOH (5 mL) was added Hydroxylamine hydrochloride(47 mg, 0.67 mmol, 3.0 eq). Then the reaction mixture was stirred atr.t. overnight. The mixture was partitioned between EA and H₂O. Thecombined organic phase was washed with water and brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to affordthe desired Intermediate 3 (30 mg). LC-MS: m/z 481.1 (M+H)⁺.

Step C:(E)-2-hydroxy-1-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)guanidine

A mixture of Intermediate 3 (30 mg, 0.06 mmol) in HCl/dioxane (5 mL, 1N)was stirred at r.t. for 1 h. The mixture was then concentrated underreduced pressure to afford the desired compound 4.

¹H NMR (DMSO-d₆): δ 7.23-7.52 (m, 12H), 7.01 (d, J=9.2 Hz, 2H), 3.81 (s,3H). LC-MS: m/z 467.2 (M+H)⁺.

Compound 201:(S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazol-1-yl)methyl2-amino-3-methylbutanoate

Step A: (S)-chloromethyl2-((tert-butoxycarbonyl)amino)-3-methylbutanoate

To a solution of Intermediate 1 (1.4 g, 6.6 mmol) in DCM/H₂O (10 mL/10mL) were added chloromethyl sulfochloridate 6 (1.3 g, 7.9 mmol, 1.2eq.), NaHCO₃(4 eq) and tetrabutylammonium hydrogensulfate (0.1 eq.). Themixture was stirred at r.t. overnight. The organic phase was separated,and the water phase was extracted with DCM (3*10 mL). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyto afford the desired product 2 as a colorless oil (1.5 g). LC-MS: m/z266.2 (M+H)⁺.

Step B:(S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazol-1-yl)methyl2-((tert-butoxycarbonyl)amino)-3-methylbutanoate

To a solution of Intermediate 3 (300 mg, mmol) in DMF (20 mL) was addedsodium hydride (3 eq.) at 0° C. (S)-chloromethyl2-((tert-butoxycarbonyl)amino)-3-methylbutanoate 2 (3 eq.) was addeddropwise after the mixture was stirred at 0° C. for 30 min. Then themixture was stirred at r.t. overnight. The mixture was poured into water(100 mL) and extracted with DCM (3*20 mL), the combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography to afford thedesired product 4 as a white solid. (240 mg)

¹H NMR (DMSO-d₆): δ 13.07 (s, 1H), 9.11 (s, 1H), 7.95 (s, 1H), 7.83 (d,J=2.8 Hz, 1H), 7.49-7.57 (m, 4H), 7.36-7.42 (m, 6H), 7.28 (d, J=8.6 Hz,2H), 7.05 (d, J=8.6 Hz, 2H), 6.14 (d, J=2.8 Hz, 1H), 5.97 (d, J=10.8 Hz,1H), 5.77 (d, J=10.8 Hz, 1H), 3.83 (s, 3H), 3.76-3.81 (m, 1H), 1.84 (dt,J=13.2, 6.8 Hz, 1H), 1.35 (s, 9H), 0.74 (d, J=6.8 Hz, 3H), 0.71 (d,J=6.8 Hz, 3H). LC-MS: m/z 704.1 (M+H)⁺

Step C:(S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazol-1-yl)methyl2-amino-3-methylbutanoate

To a solution of Intermediate 4 (220 mg, 0.31 mmol) in DCM (1 mL) wasadded HCl-dixane (4 mol/L, 5 mL) at 0° C. The mixture was stirred atr.t. for 1 h. The white precipitate was filtered off and mixed with DCM(5 mL) and aq. NaHCO₃ solution. The organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford thedesired product 5.

¹H NMR (DMSO-d₆): δ 8.14 (s, 1H), 7.75 (br. s., 1H), 7.51 (d, J=6.2 Hz,2H), 7.45 (br. s., 2H), 7.34 (br. s., 6H), 7.27 (d, J=8.4 Hz, 2H),7.10-7.23 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 5.87-6.02 (m, 2H), 3.81 (s,3H), 3.52-3.69 (m, 1H), 1.79-2.05 (m, 1H), 0.78 (br. s., 6H). LC-MS: m/z604.0 (M+H)⁺.

Compound 203:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: 3-oxo-3-(pyridin-2-yl)propanenitrile

To a solution of methyl picolinate (13 g, 95 mmol) and acetonitrile (5.8g, 142 mmol) in THF (150 ml) was added slowly NaHDMS (2 mol/L, 71 ml,142 mmol) at 0° C. Then the reaction mixture was stirred at 0° C. for0.5 h and allowed to warm up to room temperature for 2 h. The reactionwas quenched with water, adjusted with HCl (2 mol/L) to pH=7, andextracted with DCM (100 ml*3). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated invacuo to give 3-oxo-3-(pyridin-2-yl)propanenitrile (12 g, 87% yield) asa dark brown solid.

¹H NMR (CHLOROFORM-d) δ: 8.70 (dd, J=4.8, 0.6 Hz, 1H), 8.03-8.17 (m,1H), 7.92 (td, J=7.8, 1.6 Hz, 1H), 7.58 (ddd, J=7.6, 4.8, 1.4 Hz, 1H),4.40 (s, 2H). LC-MS: m/z 147.1 (M+H)⁺.

Step B: 1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine

To a solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (10 g, 68 mmol) inEtOH (80 ml) was added (4-methoxybenzyl)hydrazine hydrochloride (15.5 g,82 mmol, 1.2 eq) and triethylamine (13.8 g, 137 mmol, 2 eq.). Thereaction mixture was refluxed for 2 h under N₂ protection. Then themixture was evaporated in vacuo. The residue was dissolved in EA (100mL), washed with water, and extracted with EA (100 ml*2). The combinedorganic phase was washed with brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo to give the crude product as a yellowsolid. The crude product was suspended in t-BuOMe (100 mL), stirred for0.5 h and filtered off to give1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine as a pale yellowsolid (15.1 g, 79% yield).

¹H NMR (DMSO-d₆) δ: 8.50 (d, J=4.8 Hz, 1H), 7.77-7.83 (m, 1H), 7.73 (dd,J=7.6, 1.6 Hz, 1H), 7.11-7.26 (m, 3H), 6.84-6.90 (m, 2H), 5.89 (s, 1H),5.41 (s, 2H), 5.12 (s, 2H), 3.71 (s, 3H). LC-MS: m/z 281.2 (M+H)⁺.

Step C:4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine

To a solution of 1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine(15.0 g, 54 mmol) in acetic acid (100 mL) was added cyclohexanone (5.3g, 54 mmol, 1 eq.). The mixture was stirred at 90° C. for 1 h. Thenanother 1 eq. of cyclohexanone was added, and the mixture was stirred at90° C. for 1 h. Solvent was removed in vacuo. The resultant residue wasdissolved in EA (100 mL) and treated with saturated NaHCO₃. The organicphase was separated, and the water phase was extracted with EA (100mL*2). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography (MeOH/DCM=1/20) to give4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amineas a brown solid (6.8 g, 35% yield).

¹H NMR (DMSO-d₆) δ: 8.49 (d, J=4.4 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.65(d, J=7.8 Hz, 1H), 7.07-7.29 (m, 3H), 6.88 (d, J=8.8 Hz, 2H), 5.47 (br.s., 1H), 5.14 (s, 2H), 4.94 (br. s., 2H), 3.71 (s, 3H), 2.12 (br. s.,2H), 1.98 (br. s., 2H), 1.59 (br. s., 4H). LC-MS: m/z 361.2 (M+H)⁺.

Step D: 4-(cyclohex-1-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine

The solution of4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine(6.8 g, 19 mmol) in TFA/(CF₃SO₂)₂₀ (30 mL/10 mL) was stirred at 50° C.for 1 h. The solvent was removed in vacuo. The residue was dissolved inEA (50 mL) and treated with saturated NaHCO₃. The organic phase wasseparated, and the water phase was extracted with EA (50 mL*2). Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was dissolved in NH₃/MeOH(7 mol/L, 50 mL), and hydrazine hydrate (g, mmol, 2 eq.) was added. Themixture was stirred at r.t. overnight. Solvent was removed in vacuo andthe residue was purified by flash chromatography (MeOH/DCM 1/20) to give4-(cyclohex-1-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.6 g, 79%yield) as a brown solid. LC-MS: m/z 241.2 (M+H)⁺.

Step E:3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.6 g, 15mmol) and dimethyl 2-(4-methoxyphenyl)malonate (7.2 g, 30 mmol, 2 eq.)in xylene (50 ml) was refluxed for 8 h. The reaction mixture was cooledto room temperature. The precipitate was filtered off and washed withMeOH to give3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(4.0 g, 64% yield) as a yellow solid. LC-MS: m/z 415.2 (M+H)⁺.

Step F:5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

The solution of3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(4.0 g, 10 mmol) in POCl₃ (30 ml) in a sealed tube was stirred at 120°C. overnight. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in DCM (50 mL) andpoured into ice-water (100 mL). The mixture was adjusted to PH=7 byadding saturated NaHCO₃ solution. The organic phase was separated, andthe water phase was extracted with DCM (50 ml*2). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (eluting PE/EA=1:1) to give5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(2.8 g, 64% yield) as a yellow solid. LC-MS: m/z 451.1, 453.1 (M+H)⁺.

Step G:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(2.8 g, 6 mmol) in DCM (50 ml) was added NaOMe (6.2 mL, 5.0 mol/L inMeOH) at 0° C. The reaction mixture was stirred at 0° C. for 10 min andpoured into ice-water (100 mL). The organic phase was separated, and thewater phase was extracted with DCM (50 ml*2). The combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo to give5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(2.7 g, 97% yield) as a yellow solid.

¹H NMR (DMSO-d₆) δ: 8.70 (dt, J=4.8, 1.2 Hz, 1H), 7.91-7.96 (m, 2H),7.42-7.47 (m, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 5.82(br. s., 1H), 4.12 (s, 3H), 3.83 (s, 3H), 2.09-2.24 (m, 4H), 1.56-1.75(m, 4H). LC-MS: m/z 447.2, 449.2 (M+H)⁺.

Step H:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine(300 mg, 0.67 mmol), pyridin-2-amine (126 mg, 1.34 mmol, 2 eq.),Pd(OAc)₂ (90 mg, 0.40 mmol, 0.6 eq.), Xantphos (232 mg, 0.40 mmol, 0.6eq.) and Cs₂CO₃ (437 mg, 1.34 mmol, 2.0 eq.) in 1.4-dioxane (10 mL) wasstirred at 130° C. through microwave irradiation for 1.5 hour under N₂atmosphere. The mixture was filtered through celite, and the filtratewas concentrated in vacuo to afford the title compound.

¹H NMR (DMSO-d₆) δ: 8.67 (d, J=8.2 Hz, 1H), 8.42 (br. s., 1H), 8.12 (d,J=4.4 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.60-7.69 (m, 1H), 7.41-7.52 (m,1H), 7.24-7.39 (m, 3H), 7.20 (s, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.89-6.98(m, 1H), 5.97 (br. s., 1H), 3.82 (s, 3H), 2.20 (br. s., 4H), 1.66 (br.s., 4H). LC-MS: m/z 491.2 (M+H)⁺.

3,4-diphenyl-1H-pyrazol-5-amine

Step A: 3-oxo-2,3-diphenylpropanenitrile

To a solution of 2-phenylacetonitrile 1 (10 g, 85.3 mmol) and methylbenzoate 4 (12.2 g, 90 mmol) in THF (100 mL) was added sodium hydride(6.8 g, 170 mmol) at 0° C. After addition, the mixture was stirred atroom temperature overnight. The mixture was quenched with 1 Mhydrochloric acid to pH 6. The organic phase was dried over anhydroussodium sulfate and concentrated under reduced pressure to dryness. Theresidue was added petroleum ether (60 mL) and the turbid liquid wasstirred at room temperature for 3 h. The precipitate was collected byfiltration and dried in vacuo to afford 3-oxo-2,3-diphenylpropanenitrile2 (15.3 g) as a white solid. LC-MS: m/z 222.1 (M+H)⁺.

Step B: 3,4-diphenyl-1H-pyrazol-5-amine

A mixture of 3-oxo-2,3-diphenylpropanenitrile (15 g, 67.8 mmol),hydrazine hydrate (7.6 g, 150 mmol), acetic acid (15 mL) and the ethanol(60 mL) was heated to reflux overnight. The mixture was evaporated toremove ethanol and the residue was adjusted to pH 8 with saturatedsolution of sodium bicarbonate at 0° C. The mixture was extracted withethyl acetate (80 mL) twice, and the combined organic phase was washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo to dryness. The resulting solid was recrystallized from2-methoxy-2-methylpropane to give 3,4-diphenyl-1H-pyrazol-5-amine (16 g)as a white solid. LC-MS: m/z 236.1 (M+H)⁺.

3-(2-fluorophenyl)-4-phenyl-1H-pyrazol-5-amine

This compound was prepared according to the procedures for preparingintermediate 3,4-diphenyl-1H-pyrazol-5-amine by using compound 4 asmethyl 2-fluorobenzoate.

Step A stoichiometry: 2-phenylacetonitrile (5 g, 42.6 mmol), methyl2-fluorobenzoate (6.9 g, 45 mmol) and sodium hydride (3.4 g, 85 mmol) inTHF (60 mL) under cooling at 0° C. LC-MS: m/z 240.1 (M+H)⁺.

Step B stoichiometry: 3-(2-fluorophenyl)-3-oxo-2-phenylpropanenitrile(3.25 g, 13.6 mmol), hydrazine hydrate (1.5 g, 30 mmol), acetic acid (3mL) and the ethanol (15 mL) under heating to reflux overnight. LC-MS:m/z 254.2 (M+H)⁺.

3-phenyl-4-((²H₁₀)piperidin-1-yl)-1H-pyrazol-5-amine

Step A: 2-((²H₁₀)piperidin-1-yl)acetonitrile

The mixture of piperidine-d₁₀ (100 mg, 1.04 mmol, 1 eq.),2-bromoacetonitrile (150 mg, 1.2 eq.), and K₂CO₃ (276 mg, 2 eq.) inCH₃CN (5 mL) was stirred at 70° C. overnight. Then the mixture wascooled to r.t. and filtered, the filtrate was poured into water (30 mL)and extracted with EA (10 mL*3). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford Intermediate 2 which was directly used to the next step withoutfurther purification. LC-MS: m/z 135.0 (M+H)⁺.

Step B: 3-oxo-3-phenyl-2-((²H₁₀)piperidin-1-yl)propanenitrile

To a mixture of Intermediate 2 (115 mg, 0.86 mmol, 1 eq.) and methylbenzoate (140 mg, 1.03 mmol, 1.2 eq.) in THF (8 mL) was added NaHMDS (2Min THF, 0.52 mL, 1.2 eq.) at 0° C. The mixture was stirred at r.t.overnight. The reaction mixture was diluted with EA (10 mL) and quenchedwith saturated NH₄Cl. The organic phase was separated, washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography to afford the desiredIntermediate 3 as a white solid. LC-MS: m/z 239.1 (M+H)⁺.

Step C: 3-phenyl-4-((²H₁₀)piperidin-1-yl)-1H-pyrazol-5-amine

The mixture of Intermediate 3 (169 mg, 0.71 mmol, 1 eq.) and hydrazine(71 mg, 1.42 mmol, 2 eq.) in EtOH/AcOH (5/1.5 mL/1 mL) was refluxed for5 h. Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (5 mL) and neutralized with 10% NaHCO₃. The organicphase was separated, and the the water phase was extracted with EA (5mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography to afford the desired product 4 as a white solid.

¹H NMR (DMSO-d₆): δ 11.52 (br. s., 1H), 7.85 (d, J=7.6 Hz, 2H), 7.38 (t,J=7.6 Hz, 2H), 7.22-7.29 (m, 1H), 4.35 (br. s., 2H). LC-MS: m/z 253.1(M+H)⁺.

3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine

This compound was prepared according to the procedure for preparingintermediate 3-phenyl-4-((²H₁₀)piperidin-1-yl)-1H-pyrazol-5-amine, stepB-C, starting from 2-(piperidin-1-yl)acetonitrile.

Step B stoichiometry: 2-(piperidin-1-yl)acetonitrile (7.8 g, 62 mmol, 1eq.), methyl benzoate (9.4 g, 68 mmol, 1.1 eq.) and NaHMDS (2 M in THF,46 mL, 1.5 eq.) in THF (300 mL) at 0° C.-r.t.

Step C stoichiometry: 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile (5g, 21.902 mmol) and hydrazine hydrate (3.3 g, 65.706 mmol) in EtOH/AcOH(5/1, 30 mL/6 mL) under heating to reflux for 16 h under N₂ protection.

¹H NMR (DMSO-d₆): 1.52 (br. s., 1H), 7.82 (br. s., 2H), 7.36 (t, J=7.2Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 4.28 (br. s., 2H), 2.88 (t, J=5.0 Hz,3H), 1.55 (br. s., 3H), 1.46 (d, J=4.0 Hz, 2H). LC-MS: m/z 243.2 (M+H)+.

4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine

This compound was prepared according to the procedure for preparingintermediate 3-phenyl-4-((²H₁₀)piperidin-1-yl)-1H-pyrazol-5-amine, stepA-C, starting from 4,4-difluoropiperidine hydrochloride salt. Step Astoichiometry: 4,4-difluoropiperidine hydrochloride salt (1.0 g, 6.3mmol, 1 eq.), 2-bromoacetonitrile (761 mg, 6.3 mmol, 1 eq.),triethylamine (2.2 g, 22.2 mmol, 3.5 eq.) in THF (30 mL) under heatingat 60° C. overnight. LC-MS: m/z 161.0 (M+H)⁺. Step B stoichiometry:2-(4,4-difluoropiperidin-1-yl)acetonitrile (500 mg, 3.1 mmol, 1 eq.),methyl benzoate (467 mg, 3.4 mmol, 1.1 eq.) and NaHMDS (2 M in THF, 2.3mL, 1.5 eq.) in THF (30 mL) at 0° C.-r.t. Step C stoichiometry:2-(4,4-difluoropiperidin-1-yl)-3-oxo-3-phenylpropanenitrile (380 mg,1.44 mmol, 1 eq.) and hydrazine hydrate (144 mg, 2.88 mmol, 2 eq.) inEtOH/AcOH (5/1, 15 mL/3 mL) under heating to reflux for 6 h. LC-MS: m/z279.1 (M+H)⁺.

4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine

Step A: 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine

A suspension of amino-pyrazole (10 g, 62.9 mmol) and cyclohexanone (13mL, 126 mmol) and 4-methylbenzenesulfonic acid hydrate (11.4 g, 62.9mmol) in 1.4-dioxane (50 mL) was stirred for 8 hours at 90° C. Theprecipitate was collected by filtration and washed with acetonitrile toafford crude product which was recrystallized from methanol to afford4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (4.18 g) as white solid.

¹H NMR (Chloroform-d): δ 7.51 (d, J=6.98 Hz, 2H), 7.31-7.43 (m, 3H),5.81 (br. s., 1H), 2.19 (br. s., 2H), 1.98 (d, J=1.88 Hz, 2H), 1.59-1.70(m, 4H). LC-MS: m/z 240.1 (M+H)⁺.

4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine

Step A: 1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine

A mixture of 3-oxo-3-phenylpropanenitrile (14.5 g, 0.1 mmol),(4-methoxybenzyl)hydrazine (15.2 g, 0.1 mmol), acetic acid (40 mL) andethanol (150 mL) was heated to 85° C. overnight. The mixture was cooledto room temperature and poured to water (300 mL). The mixture wasbasified by adding aqueous sodium hydroxide at 0° C. to pH 7-8. Theresulting suspension was filtrated. The filter cake was washed withwater, dried in vacuo to afford1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine (14.4 g) as a whitesolid.

¹H NMR (Chloroform-d): δ 7.79 (d, J=8.8 Hz, 2H), 7.38-7.42 (m, 2H),7.28-7.38 (m, 1H), 7.19 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.91(s, 1H), 5.24 (s, 2H), 3.81 (s, 3H). LC-MS: m/z 280.1 (M+H)⁺.

Step B:4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine

A mixture of 1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine (9 g, 32.5mmol) and cyclohexanone (6.4 g, 65.0 mmol) in acetic acid (50 mL) wasstirred at room temperature for 16 h. The mixture was poured to water(150 mL). Aqueous sodium hydroxide was added into the mixture at 0° C.to pH 7-8. The resulting mixture was extracted with ethyl acetate (60mL) three times. The combined organic phase was washed with brine, driedover anhydrous sodium sulfate and evaporated to dryness. The residue waspurified with column chromatography (ethyl acetate:petroleum ether=1:3)on silica gel to afford4-cyclohexenyl-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine (6.5 g)as a white solid. LC-MS: m/z 360.2 (M+H)⁺.

Step C: 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine

A mixture of4-cyclohexenyl-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine (6.0 g,16.7 mmol) and trifluoromethanesulfonic anhydride (12 mL) intrifluoroacetic acid (36 mL) was stirred at 30° C. for 2 h. The mixturewas poured to water (50 mL). Aqueous sodium hydroxide was added into themixture at 0° C. to pH 7-8. The mixture was extracted with ethyl acetate(60 mL) three times. The combined organic phase was washed with brine,dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was purified with column chromatography(methanol:dichloromrthane=1:20) on silica gel to afford4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (2.6 g) as a white solid.

¹H NMR (Chloroform-d) δ 7.51 (d, J=6.98 Hz, 2H), 7.31-7.43 (m, 3H), 5.81(br. s., 1H), 2.19 (br. s., 2H), 1.98 (d, J=1.88 Hz, 2H), 1.59-1.70 (m,4H). LC-MS: m/z 240.1 (M+H)⁺.

4-methoxy-1,3,5-triazin-2-amine

Step A: 4-chloro-1,3,5-triazin-2-amine

2,4-dichloro-1,3,5-triazine (8.0 g, 53.3 mmol) was added in portions to200 mL of NH₄OH at −20° C. After addition, the mixture was stirred at−20° C. for 10 mins, and then filtered, washed with water and dried togive 4-chloro-1,3,5-triazin-2-amine (5.7 g) as a yellow solid which wasused to the next step without further purification. LC-MS: m/z 131.1(M+H)⁺.

Step B: 4-methoxy-1,3,5-triazin-2-amine

To the solution of 4-chloro-1,3,5-triazin-2-amine (5.7 g, 44.0 mmol) inMeOH (100 mL) cooled to 0° C. was added CH₃ONa (35.2 mL, 176.1 mmol, 5.0M) dropwise. Then the mixture was stirred at room temperature for 1 h.Half of the solvent was removed by vacuum, and the precipitate wasfiltered, washed with water to afford 4-methoxy-1,3,5-triazin-2-amine asa white solid (1.0 g). LC-MS: m/z 127.1 (M+H)⁺.

N2-methyl-1,3,5-triazine-2,4-diamine

Step A: The mixture of 4-chloro-1,3,5-triazin-2-amine (200 mg, 1.5 mmol)in MeNH₂/THF (2 mol/L, 10 mL) was stirred at r.t. for 10 min. Themixture was concentrated in vacuo, and the residue was purified by flashchromatography (DCM/MeOH 10/1) to afford the desired product as a whitesolid. (106 mg). LC-MS: m/z 125.9 (M+H)⁺.

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine

Step A: 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

A mixture of compound 1 (10 g, 0.089 mmol) and Cs₂CO₃ (1.9 g, 0.116mmol) in DMF (10 mL) was stirred at r.t. for 16 h. The mixture wasdiluted with water (20 mL) and extracted with EA (20 mL×3). The organiclayer was dried, concentrated and purified by silica gel chromatography(PE:EA=3:1) to afford compound 2 (9 g) as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d): δ 0.01-0.03 (m, 9H) 0.91-0.99 (m, 2H)3.59-3.66 (m, 2H) 5.53 (s, 2H) 7.01 (d, J=2.69 Hz, 1H) 7.69 (d, J=2.69Hz, 1H). LC-MS: m/z 244.5 (M+H)⁺.

Step B: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine

The compound 2 (9 g, 0.037 mmol) and Pd/C (0.9 g) in MeOH (30 mL) wasstirred at r.t. for 16 h under H₂ atmosphere. The mixture was filteredand concentrated to give the crude product which was directly used tothe next step without further purification. LC-MS: m/z 214.5 (M+H)⁺.

2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine

This compound was prepared according to the procedures for preparing1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine by usingintermediate 1 as 4-nitro-2H-1,2,3-triazole.

¹H NMR (DMSO-d₆): δ 7.00 (s, 1H), 5.35 (s, 2H), 5.13 (s, 2H), 3.49-3.58(m, 2H), 0.69-0.89 (m, 2H), −0.04 (s, 9H). LC-MS: m/z 215.2 (M+H)⁺.

1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine

Step A: The mixture of malononitrile (1.9 g, 0.028 mmol) and(4-methoxybenzyl)hydrazine hydrochloride (5.4 g, 0.028 mmol) in EtOH (20mL) and TEA (3 mL) was heated to reflux for 16 h. The mixture wasconcentrated to dryness. The residue was suspended in water andextracted with EA (10 mL×3). The combined organic layers were dried andconcentrated to give the crude product which was directly used to thenext step without further purification. LC-MS: m/z 219.5 (M+H)⁺.

Methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate

To a solution of methyl 2-(3,4-dihydroxyphenyl)acetate (4 g, 0.022 mol)in DMF (20 mL) were added 1,2-dibromoethane (4.09 g, 0.022 mol) andK₂CO₃ (6 g, 0.044 mol). The reaction mixture was heated to 80° C. for 4h. The reaction mixture was then poured into water, extracted with ethylacetate, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by column chromatography on silica gel(eluting PE/EA=10:1) to give the desired product (1.3 g).

¹H NMR (DMSO-d₆): δ 6.73-6.81 (m, 3H), 6.65-6.73 (m, 1H), 4.16-4.27 (m,5H), 3.55 (s, 3H). LC-MS: m/z 223.1 (M+H)⁺.

3-(tert-butyldimethylsilyloxy)pyridin-2-amine

Step A: To a mixture of 2-aminopyridin-3-ol (220 mg, 2 mmol),1H-imidazole (204 mg, 3 mmol) in chloroform (20 mL) was addedtert-butylchlorodimethylsilane (302 mg, 2 mmol) slowly at roomtemperature. Then the reaction mixture was stirred at room temperatureovernight. The mixture was evaporated to dryness. The residue waspurified by column chromatography on silica gel(methanol:dichloromethane=1:50) to afford3-(tert-butyl-dimethylsilyloxy) pyridin-2-amine (360 mg) as a whitesolid. LC-MS m/z: 225.1 (M+H)⁺.

5-((tert-butyldimethylsilyl)oxy)pyridin-2-amine

This compound was prepared according to3-(tert-butyldimethylsilyloxy)pyridin-2-amine by using Intermediate 1 as6-aminopyridin-3-ol in step A. LC-MS m/z: 225.1 (M+H)⁺.

General Procedure 2a

Step A: methyl 3-oxo-2-(quinolin-6-yl)butanoate

To a solution of methyl 2-(quinolin-6-yl)acetate 1 (148 g, 0.736 mol,1.0 eq.) in THF (1 L) was added LDA (1.5 M in THF, 589 mL, 0.883 mol,1.2 eq.) dropwise at −30˜−35° C. The mixture was stirred at −30˜−35° C.for 30 min and acetyl chloride (56 mL, 0.788 mol, 1.05 eq.) was addeddropwise. Then the mixture was stirred at rt for 6 h. The mixture waspoured slowly to saturated NH₄Cl and extracted with EA (3*350 mL). Thecombined organic phase was washed with brine, dried over anhydrous MgSO₄and concentrated in vacuo. The residue was purified by flashchromatography to afford the desired Intermediate 2 as a brown oil (150g, 84% yield).

Step B: Compound 204:5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 2 (150 g) and 4 (1.0 eq) in AcOH (700 mL)was stirred at 90° C. for 4 h. A solid was filtered off and washed withEA (3*100 mL) to afford the desired product 3.

¹H NMR (DMSO-d₆) δ: 12.06 (s, 1H), 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.40(d, J=7.5 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.76(dd, J=8.6, 1.9 Hz, 1H), 7.54-7.59 (m, 1H), 7.24-7.51 (m, 10H), 2.25 (s,3H). LC-MS: m/z 429.3 (M+H)⁺.

Compound 205:2-(2-fluorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 4 as 3-(2-fluorophenyl)-4-phenyl-1H-pyrazol-5-amine e instep B.

Step B: The solution of 3-(2-fluorophenyl)-4-phenyl-1H-pyrazol-5-amine(50 mg, 0.20 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (62.4 mg,0.26 mmol) in AcOH (2 ml) was stirred at 100° C. for 1 hour. Aftercooling to room temperature, saturated NaHCO₃ was added till pH>7. Themixture was extracted with DCM (50 mL), washed with brine (20 mL), driedover anhydrous sodium sulfate and concentrated to dryness. The residuewas purified by prep-TLC (DCM:MeOH=25:1) to obtain2-(2-fluorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 12.19 (br. s., 1H), 8.95 (dd, J=4.2, 1.7 Hz, 1H),8.41 (d, J=7.5 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.98 (d, J=1.9 Hz, 1H),7.76 (dd, J=8.9, 1.9 Hz, 1H), 7.58 (dd, J=8.2, 4.2 Hz, 1H), 7.45-7.54(m, 2H), 7.36-7.43 (m, 2H), 7.24-7.35 (m, 4H), 7.16-7.24 (m, 1H), 2.28(s, 3H). LC-MS: m/z 447.1 (M+H)⁺.

Compound 206:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 4 as 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine in stepB.

Step B: methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol) and5-phenyl-4-(piperidin-1-yl)-1H-pyrazol-3-amine (200 mg, 0.82 mmol) weredissolved in AcOH (8 ml). The mixture was stirred at 95° C. for 10 min.After cooling to room temperature, the mixture was poured into water andextracted with EA (50 ml*3). The EA layer was concentrated to dryness.The residue was basified with NaHCO₃aq. solution and filtered. Thefilter cake was purified by prep-HPLC to give the title compound.

¹H NMR (DMSO-d₆) δ: 11.52 (br. s., 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H),8.34-8.44 (m, 1H), 8.02-8.19 (m, 3H), 7.95 (d, J=1.9 Hz, 1H), 7.74 (dd,J=8.9, 1.9 Hz, 1H), 7.58 (dd, J=8.2, 4.2 Hz, 1H), 7.31-7.51 (m, 3H),3.11 (t, J=4.8 Hz, 4H), 2.34 (s, 3H), 1.68 (br. s., 4H), 1.50-1.64 (m,2H). LC-MS: m/z 436.4 (M+H)⁺.

Compound 207:3-(4,4-difluoropiperidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 4 as4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B: The solution of4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.72mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (262.2 mg, 1.08 mmol)in AcOH (3 ml) was stirred at 100° C. for 1 hour. After cooling to roomtemperature, saturated NaHCO₃ was added till pH>7. The mixture wasextracted with DCM (60 mL), washed with brine (20 mL), dried overanhydrous sodium sulfate and concentrated to dryness. The residue waspurified by prep-TLC (DCM:MeOH=25:1) to obtain3-(4,4-difluoropiperidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.71 (s, 1H), 8.94 (d, J=2.7 Hz, 1H), 8.39 (d,J=7.8 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.94 (s,1H), 7.74 (dd, J=8.7, 2.0 Hz, 1H), 7.58 (dd, J=8.2, 4.2 Hz, 1H), 7.52(t, J=7.4 Hz, 2H), 7.44 (t, J=7.3 Hz, 1H), 3.24 (m, 4H), 2.33 (s, 3H),2.04-2.22 (m, 4H). LC-MS: m/z 472.2 (M+H)⁺.

Compound 208:3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 1 as methyl 2-(quinoxalin-6-yl)acetate in step A andIntermediate 4 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine instep B.

Step B: The solution of4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (60 mg, 0.25 mmol)and methyl 3-oxo-2-(quinoxalin-6-yl)butanoate (79.6 mg, 0.33 mmol) inAcOH (5 ml) was stirred at 100° C. for 1 hour. After cooling to roomtemperature, solvent was removed by vacuum, and saturated NaHCO₃ wasadded till pH>7. The mixture was diluted with DCM (60 mL), washed withbrine (20 mL), dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by prep-TLC (DCM:MeOH=25:1) to obtain3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.90 (br. s., 1H), 9.00 (br. s., 2H), 7.48-8.26 (m,8H), 5.89 (br. s., 1H), 2.10-2.52 (m, 7H), 1.72 (br. s., 4H). LC-MS: m/z434.1 (M+H)⁺.

Compound 209:6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A andIntermediate 4 as 3,4-diphenyl-1H-pyrazol-5-amine in step B.

Step B: The mixture of methyl 2-(4-methoxyphenyl)-3-oxobutanoate (300mg, 1.3 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (206 mg, 0.85 mmol) inAcOH (15 mL) was stirred at 100° C. for 2 h to afford the titlecompound.

¹H NMR (DMSO-d₆) δ: 11.88 (s, 1H), 7.37-7.49 (m, 5H), 7.28-7.36 (m, 5H),7.21-7.28 (m, 2H), 6.95-7.05 (m, 2H), 3.80 (s, 3H), 2.17 (s, 3H). LC-MS:m/z 408.0 (M+H)⁺.

Compound 210:6-(4-ethoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 1 as methyl 2-(4-ethoxyphenyl)acetate in step A andIntermediate 4 as 3,4-diphenyl-1H-pyrazol-5-amine in step B.

Step B: The solution of 3,4-diphenyl-1H-pyrazol-5-amine (148 mg, 0.63mmol) and methyl 2-(4-ethoxyphenyl)-3-oxobutanoate (150 mg, 0.63 mmol)in AcOH (5 ml) was stirred at 100° C. for 4 hour. After cooling to roomtemperature, the reaction mixture was filtered and washed with EA (6 mL)and MeOH (0.5 mL) to obtain title compound.

¹H NMR (DMSO-d₆) δ: 11.88 (s, 1H), 7.36-7.49 (m, 5H), 7.27-7.36 (m, 5H),7.19-7.26 (m, 2H), 6.93-7.02 (m, 2H), 4.07 (q, J=7.0 Hz, 2H), 2.17 (s,3H), 1.36 (t, J=7.2 Hz, 3H). LC-MS: m/z 422.0 (M+H)⁺.

Compound 211:6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a, step A-B,starting from methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate instep A.

Step A: methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate

To a solution of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate(1.3 g, 6.3 mmol) in THF (15 ml) was added slowly LDA (3.2 ml, 2 mmol/mlin THF) at −30° C. Then acetyl chloride (730 mg, 9.5 mmol) was addedslowly. The reaction mixture was stirred for 30 mins at −30° C. andallowed to room temperature for 1 h. The mixture was poured into water,extracted over ethyl acetate, dried over anhydrous Na₂SO₄, filtered, andconcentrated to give the crude product (1.3 g, crude) as a yellowliquid, which was used directly to the next step without furtherpurification.

Step B:6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate (crude 400 mg)and 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml)was heated to 120° C. overnight. The reaction mixture was cooled to roomtemperature to give the desired product6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.88 (s, 1H), 7.38-7.52 (m, 5H), 7.24-7.38 (m, 5H),6.91 (d, J=8.1 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 6.77 (d, J=8.2, 2.0 Hz,1H), 4.29 (s, 4H), 2.19 (s, 3H). LC-MS: m/z 435.9 (M+H)⁺.

Compound 212:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A andIntermediate 4 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine instep B.

Step B: The solution of4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84 mmol)and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (371.5 mg, 1.67 mmol) inAcOH (5 ml) was stirred at 100° C. for 1 hour. After cooling to roomtemperature, solvent was removed by vacuum, and saturated NaHCO₃ wasadded to pH>7 to obtain3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.62 (s, 1H), 7.72-7.85 (m, 2H), 7.34-7.55 (m, 3H),7.19-7.31 (m, 2H), 6.93-7.07 (m, 2H), 5.84 (br. s., 1H), 3.81 (s, 3H),2.17-2.32 (m, 5H), 1.98-2.12 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z412.3 (M+H)⁺.

Compound 213:3-(4,4-difluoropiperidin-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2a by usingIntermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A andIntermediate 4 as4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B: The mixture of4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine (321 mg, 1.4mmol) and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (200 mg, 0.72 mmol)in AcOH (20 mL) was stirred at 120° C. for 2 h to afford the titlecompound.

¹H NMR (CHLOROFORM-d) δ: 7.51 (br. s., 5H), 7.24 (d, J=8.6 Hz, 2H), 6.98(d, J=8.6 Hz, 2H), 3.85 (s, 3H), 3.69 (br. s., 4H), 3.18 (br. s., 2H),2.37 (s, 3H), 2.18 (s, 2H). LC-MS: m/z 451.3 (M+H)⁺.

General Procedure 2b

Step A: methyl 3-oxo-2-(quinolin-6-yl)butanoate

To a solution of methyl 2-(quinolin-6-yl)acetate (14.8 g, 73.6 mmol, 1.0eq.) in THF (100 mL) was added LDA (1.5 M in THF, 60 mL, 88.3 mmol, 1.2eq.) dropwise at −30˜−35° C. The mixture was stirred at −30˜−35° C. for30 min and acetyl chloride (5.6 mL, 78.8 mmol, 1.05 eq.) was addeddropwise. Then the mixture was stirred at r.t. for 6 h. The mixture waspoured slowly to saturated NH₄Cl and extracted with EA (3×30 mL). Thecombined organic phase was washed with brine, dried over anhydrous MgSO₄and concentrated in vacuo to get the title Intermediate 2 which wasdirectly used to the next step without further purification.

Step B:5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of methyl 3-oxo-2-(quinolin-6-yl)butanoate (1.98 g, 8.17mmol) and 3-phenyl-1H-pyrazol-5-amine (1 g, 6.28 mmol) in 1,4-dioxane(10 ml) and AcOH (2 ml) was refluxed for 16 hours under N₂ protection.The mixture was cooled to the room temperature, concentrated, andneutralized with saturated sodium hydrogen carbonate solution to adjustto pH 7. The precipitates were collected by filtration, washed withpetroleum ether and dried to give the Intermediate 3 (600 mg, 27%yield).

¹H NMR (DMSO-d₆) δ: 12.56 (br. s., 1H), 8.94 (dd, J=4.25, 1.61 Hz, 1H),8.39 (d, J=7.63 Hz, 1H), 7.99-8.10 (m, 3H), 7.96 (d, J=1.76 Hz, 1H),7.75 (dd, J=8.66, 1.91 Hz, 1H), 7.57 (dd, J=8.36, 4.25 Hz, 1H),7.46-7.53 (m, 2H), 7.40-7.46 (m, 1H), 6.67 (s, 1H), 2.26 (s, 3H).

Step C:5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 3 (500 mg, 1.42 mmol) and K₂CO₃ (393 mg,2.84 mmol) in DMF (15 ml) at ambient temperature was added(2-(chloromethoxy)ethyl)trimethylsilane (473 mg, 2.84 mmol) dropwise.The mixture was stirred for 10 min at ambient temperature and heated to100° C. overnight. The mixture was cooled to the room temperature,washed with saturated sodium hydrogen carbonate solution, and extractedwith DCM (2×30 mL). The combined organic layers were washed with brine(3×20 ml), dried over anhydrous sodium sulfate, and concentratedinvacuo. The residue was purified by silica gel column eluting withDCM/MeOH (30/1 to 10/1) to obtain the Intermediate 4 as a white solid(350 g, 51% yield).

Step D:3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 4 (350 mg, 0.725 mmol) in DCM (5 ml) atambient temperature was added NBS (163 mg, 0.92 mmol). The resultantmixture was stirred for 3 hours at ambient temperature, washed withwater, and extracted with DCM (20 mL). The combined organic layers werewashed with brine (20 ml), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=20/1) to obtain the Intermediate 5 (250 mg, 61% yield). LC-MS:m/z 561.1 (M+H)⁺.

The following compounds were prepared according to General procedure 2b,step E and step F, starting from intermediate 5.

Compound 215:3-(cyclopent-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(150 mg, 0.27 mmol),2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (155.0mg, 0.80 mmol), Bis(triphenylphosphine)palladium(II) chloride (19.2 mg,0.03 mmol) and cesium carbonate (174.8 mg, 0.53 mmol) in 1,4-dioxane/H₂O(11 mL, 10:1) under heating at 100° C. for 1 hour through microwaveirradiation under nitrogen atmosphere. LC-MS: m/z 549.3 (M+H)⁺.

Step F: To the solution of3-(cyclopent-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.09 mmol) in DCM (0.5 mL) cooled at 0° C. was added TFA (1 mL)dropwise. Then the mixture was stirred at room temperature for 2 hours.The mixture was concentrated, and NH₄OH added till pH>7. The mixture wasdiluted with DCM (60 mL), washed with water (15 mL) and brine (15 mL),dried over anhydrous sodium sulfate, and concentrated to obtain3-(cyclopent-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.76 (br. s., 1H), 8.85-9.08 (m, 1H), 8.39 (d,J=7.8 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.96 (s, 1H), 7.68-7.79 (m, 3H),7.57 (dd, J=7.9, 4.2 Hz, 1H), 7.39-7.52 (m, 3H), 5.94 (br. s., 1H), 2.54(br. s., 2H), 2.43 (br. s., 2H), 2.30 (s, 3H), 1.88-2.11 (m, 2H). LC-MS:m/z 419.2 (M+H)⁺.

Compound 216:3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step E stoichiometry:3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.36 mmol),2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (149.8mg, 0.72 mmol), bis(triphenylphosphine)palladium(II) chloride (56.2 mg,0.08 mmol) and cesium carbonate (234.6 mg, 0.72 mmol) in 1,4-dioxane/H₂O(16 mL, 10:1) under heating at 100° C. for 1 hour through microwaveirradiation under nitrogen atmosphere. LC-MS: m/z 563.3 (M+H)⁺.

Step F: To the solution of3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(180 mg, 0.32 mmol) in DCM (0.5 mL) cooled to 0° C. was added TFA (2 mL)dropwise. The mixture was then stirred at room temperature for 2 hours.The mixture was concentrated, and NH₄OH added till pH>7. The mixture wasdiluted with DCM (120 mL), washed with water (30 mL) and brine (30 mL),dried over anhydrous sodium sulfate and concentrated to dryness toobtain3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.80 (s, 1H), 8.94 (dd, J=4.0, 1.6 Hz, 1H), 8.39(d, J=7.3 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H),7.78-7.84 (m, 2H), 7.74 (dd, J=8.9, 1.9 Hz, 1H), 7.58 (dd, J=8.3, 4.3Hz, 1H), 7.45-7.52 (m, 2H), 7.39-7.45 (m, 1H), 5.88 (br. s., 1H), 2.31(s, 3H), 2.23 (br. s., 2H), 2.09 (br. s., 2H), 1.72 (br. s., 4H). LC-MS:m/z 433.4 (M+H)⁺.

Compound 217:3-(3,4-dihydro-2H-pyran-6-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: A mixture of3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.116 mmol),2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(49 mg, 0.232 mmol), Pd(dppf)Cl₂ (8.4 mg, 0.012 mmol), and NaHCO₃(19 mg,0.232 mmol) in dioxane (9 ml) and H₂O (3 ml) was heated to 100° C. for 4h under N₂. The mixture was concentrated to dryness to give the desiredproduct.

¹H NMR (METHANOL-d₄) δ: 8.90 (dd, J=4.3, 1.6 Hz, 1H), 8.42 (d, J=8.1 Hz,1H), 8.13 (d, J=8.9 Hz, 1H), 7.95-8.02 (m, 1H), 7.79-7.91 (m, 3H), 7.59(dd, J=8.2, 4.4 Hz, 1H), 7.38-7.50 (m, 3H), 4.97 (t, J=3.6 Hz, 1H),4.12-4.22 (m, 2H), 2.36 (s, 3H), 2.15-2.27 (m, 2H), 1.90-2.04 (m, 2H).LC-MS: m/z 435.0 (M+H)⁺.

3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2b by usingIntermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A.

¹H NMR (CHLOROFORM-d) δ: 7.89-7.93 (m, 2H), 7.45-7.51 (m, 3H), 7.18-7.27(m, J=8.3 Hz, 2H), 6.95-7.06 (m, J=8.3 Hz, 2H), 5.90 (br. s., 2H), 3.88(s, 3H), 3.74-3.82 (m, 2H), 2.42 (s, 3H), 0.99-1.08 (m, 2H), 0.03-0.06(m, 9H). LC-MS: m/z 468.2 (M+H)⁺.

Compound 218:3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2b (step E-F)by using Intermediate 5 as3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-oneand Intermediate 9 as2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instep E.

Step E: A mixture of3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.185 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(194.39 mg, 0.925 mmol), PdCl₂(PPh₃)₂ (27.07 mg, 0.037 mmol), and Cs₂CO₃(180.54 mg, 0.555 mmol) in 1,4 dioxane (3 ml) and water (0.3 ml) washeated at 100° C. for 1 hour through microwave irradiation. The mixturewas cooled to the room temperature and poured into saturated sodiumhydrogen carbonate solution. The resulting mixture was extracted withEtOAc (30 mL), washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=20/1) to obtain3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg) as a white solid. LC-MS: m/z 544.2 (M+H)⁺.

Step F: To a solution of3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)ethyl)pyrazolo[1,5-a]pyridin-7(4H)-one (40 mg, 0.074 mmol) in DCM (1ml) was added TFA (3 ml) dropwise at 0° C. The mixture was stirred forovernight at ambient temperature and concentrated to dryness. Theresidue was washed with saturated sodium hydrogen carbonate solution andextracted with DCM (20 ml). The organic layer was washed with brine (20ml), dried over anhydrous sodium sulfate, and concentrated in vacuotoobtain the title compound.

¹H NMR (DMSO-d₆) δ: 11.78 (s, 1H), 7.72-7.81 (m, 2H), 7.40-7.51 (m, 3H),7.19-7.29 (m, 2H), 6.95-7.06 (m, 2H), 5.93 (s, 1H), 4.26 (d, J=2.42 Hz,2H), 3.79-3.86 (m, 5H), 2.23 (s, 3H), 2.12-2.18 (m, 2H). LC-MS: m/z414.0 (M+H)⁺.

Compound 219:3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2b (step E-F)by using Intermediate 5 as3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-oneand Intermediate 9 as2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instep E.

Step E: A mixture of3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.37 mmol),2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(156 mg, 0.74 mmol), Pd(dppf)Cl₂ (27 mg, 0.037 mmol), and Cs₂CO₃ (241mg, 0.74 mmol) in dioxane (9 ml) and H₂O (3 ml) was heated to 100° C.for 4 h under N₂. The mixture was concentrated to dryness. The residuewas purified by prep-TLC (eluting PE/EA=1:1) to give the desired product(40 mg, 20% yield). LC-MS: m/z 544.3 (M+H)⁺.

Step F: A solution of3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.074 mmol) in CH₂Cl₂/TFA (V:V=3:1, 8 ml) was stirred for 30mins. Then the reaction mixture was concentrated to dryness. The residuewas dissolved in MeOH (10 ml), basified with ammonia (3 ml), andconcentrated in vacuo to give the desired product.

¹H NMR (METHANOL-d₄) δ: 7.86 (br. s., 2H), 7.45 (br. s., 3H), 7.20-7.33(m, J=8.1 Hz, 2H), 6.90-7.11 (m, J=7.8 Hz, 2H), 6.13 (br. s., 1H), 4.06(br. s., 2H), 3.91 (t, J=5.4 Hz, 2H), 3.86 (s, 3H), 2.41 (br. s., 2H),2.30 (s, 3H). LC-MS: m/z 414.0 (M+H)⁺.

Compound 220:6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 2b (step E-F)by using Intermediate 5 as3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-oneand compound 9 as (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid instep E.

Step E: To a sealed tube charged with3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.37 mmol), (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid(395 mg, 1.48 mmol), PdCl₂(PPh₃)₂ (259 mg, 0.37 mmol), and Cs₂CO₃ (482mg, 1.480 mmol) was added DMF (5 ml) and water (0.5 ml). The mixture wasstirred for 1 hour at 120° C. through microwave irradiation. Thereaction mixture was cooled to the room temperature, diluted withsaturated sodium hydrogen carbonate solution (30 mL), and extracted withEtOAc (30 mL). The organic phase was washed with brine (20 ml), driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by prep-TLC (DCM/MeOH=50/1) to obtain6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(70 mg) as a white solid. LC-MS: m/z 527.2 (M+H)⁺.

Step F: A solution of6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(30 mg, 0.057 mmol) in DMSO was warmed up to 150° C. in a sealed tubethrough microwave irradiation for 2 hours. The reaction mixture wasdiluted with saturated sodium hydrogen carbonate solution (20 mL) andextracted with EtOAc (20 mL). The organic phase was washed with brine(20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain the title compound.

¹H NMR (DMSO-d₆) δ: 11.63 (br. s., 1H), 11.02 (br. s., 1H), 7.61-7.71(m, 2H), 7.31-7.39 (m, 3H), 7.24 (d, J=8.60 Hz, 2H), 6.99 (d, J=8.87 Hz,2H), 6.84-6.92 (m, 2H), 5.97-6.06 (m, 1H), 3.80 (s, 3H), 2.18 (s, 3H).LC-MS: m/z 397.0 (M+H)⁺.

General Procedure 3

Step A: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate

To the solution of Intermediate 1 (36 g, 0.2 mol) and HMPA (7.2 g, 0.02mol) in THF at −78° C. was added LDA (2M in THF; 100 ml, 0.2 mol) over20 min. After stirring for 1 hour at −78° C., 2-(benzyloxy)acetylchloride (36.8 g, 0.2 mol) was added dropwise with a funnel. The mixturewas warmed up to room temperature overnight. Saturated NH₄Cl aqueoussolution was added. The resultant mixture was extracted with DCM (3×50ml). The combined organic layers were washed with saturated NaCl (50ml), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel column (PE/EtOAc=20/1) to give Intermediate 2(38 g, 58%) as a brown oil.

Step B:5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Intermediate 2 (38 g, 0.166 mol) and 3,4-diphenyl-1H-pyrazol-5-amine (40g, 0.174 mol) were dissolved in AcOH (300 ml). The mixture was warmed upto 95° C. for 4 h. After cooling to room temperature, the solids werecollected by filtration, wash with EtOAc, and dried under vacuum to giveIntermediate 3 (28 g, 47% yield) as a white solid.

¹H NMR (DMSO-d₆) δ: 11.99 (br. s., 1H), 7.20-7.50 (m, 17H), 6.97 (d,J=8.8 Hz, 2H), 4.41 (s, 2H), 4.30 (s, 2H), 3.81 (s, 3H). LC-MS: m/z514.3 (M+H)⁺.

Step C: Compound 221:5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 3 (534 mg, 1 mmol) in DCM was added BCl₃(1.0 M in DCM, 3 ml, 3 mmol) at 0° C. The mixture was stirred at 0° C.for 4 hours. The reaction was quenched by careful adding MeOH andconcentrated. The residue was mixed with sodium hydrogen carbonatesolution and ethyl acetate with stirring for 30 min. The precipitateswere filtered, wash with ethyl acetate, and dried under vacuum to giveIntermediate 4 (400 mg, 94% yield).

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 7.39-7.54 (m, 5H), 7.21-7.39 (m, 7H),6.93-7.06 (m, 2H), 5.59 (t, J=5.5 Hz, 1H), 4.30 (d, J=5.4 Hz, 2H), 3.82(s, 3H). LC-MS: m/z 424.3 (M+H)⁺.

Step D:5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a suspension of Intermediate 4 (88 g, 0.208 mol) in DCM (500 ml) wasadded SOCl₂ (120 ml) with a funnel. The mixture was stirred at roomtemperature for 1 hour. The precipitates were filtered, washed withethyl acetate, and dried under vacuum to give Intermediate 5 (110 g) asa off-white solid which was directly used to the next step withoutfurther purification.

Step E: Compound 222:5-(aminomethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 5 (200 g, 0.453 mol) and NH₃ (7.0M in MeOH,2500 ml, 17 mol) in a autoclave was stirred at 60° C. overnight. Theprecipitates were stirred in a mixed solution (50 ml, DMF:MeOH=1:1) at45° C. for 4 h give the title compound 6.

¹H NMR (DMSO-d₆) δ: 11.97 (br. s., 1H), 8.38 (br. s., 3H), 7.29-7.59 (m,12H), 7.06 (d, J=8.9 Hz, 2H), 3.90 (br. s., 2H), 3.83 (s, 3H). LC-MS:m/z 423.1 (M+H)⁺.

Compound 223:5-(aminomethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General Procedure 3 by usingIntermediate 1 as methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetatein step A.

Step A: A solution of LDA (2M in THF; 14.1 ml, 28.1 mmol) was added over20 min to the solution of methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate (3.9 g, 18.8 mmol) andHMPA (671 mg, 3.75 mmol) in THF at −78° C. After stirring for 1 hour at−78° C., 2-(benzyloxy)acetyl chloride (4.14 g, 22.5 mmol) was addeddropwise with a funnel. The mixture was warmed up to room temperatureovernight. Saturated aqueous NH₄Cl solution was added, and extractedwith DCM (3×50 ml), The combined organic layers were washed withsaturated NaCl (50 ml) and dried over Na₂SO₄. The residue was purifiedby column silica gel chromatography (PE/EtOAc=20/1) to get methyl4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate(2.6 g) as a yellow oil. LC-MS: m/z 357.1 (M+H)⁺.

Step B: methyl4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate(600 mg, 1.68 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (356 mg, 1.52mmol) was dissolved in AcOH (10 ml). The resultant mixture was warmed upto 100° C. for 16 h. The reaction was then cooled to room temperature,basified with saturated sodium hydrogen carbonate solution, andextracted with EtOAc (20 mL). The organic phase was washed with brine(20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue was purified by silica gel column (DCM:MeOH=30:1) to get5-((benzyloxy)methyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(400 mg) as a white solid. LC-MS: m/z 542.2 (M+H)⁺.

Step C: To a tube charged with 5-((benzyloxy)methyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 g, 0.37 mmol) was added BCl₃ (5 ml, 5 mmol, 1.0M in DCM) at 0° C.The mixture was stirred at room temperature for 4 hours. The reactionwas quenched with MeOH and concentrated. The residue was basified withsodium hydrogen carbonate solution, extracted with DCM, and concentratedunder vacuum to get6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 g) as a white solid. LC-MS: m/z 451.2 (M+H)⁺.

Step D: To a suspension of6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg, 0.264 mmol) in DCM (5 ml) was added SOCl₂ (63 mg, 0.453 mmol)dropwise at 0° C. The resultant mixture was stirred at room temperaturefor 3 hours. The reaction was quenched by adding saturated sodiumhydrogen carbonate solution and extracted with DCM (20 mL). The organicphase was washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated invacuo. The residue was purified by silicagel column (PE:EA=1:1) to get5-(chloromethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(90 mg) as a yellow solid. LC-MS: m/z 470.1 (M+H)⁺.

Step E: A mixture of5-(chloromethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(20 mg, 0.042 mmol) in 7N NH₃/MeOH (3 ml) in a sealed tube was stirredat 100° C. overnight to afford the title compound.

¹H NMR (DMSO-d₆) δ: 8.11 (br. s., 2H), 7.44 (br. s., 4H), 7.37 (br. s.,4H), 6.86-7.00 (m, 2H), 6.83 (br. s., 1H), 4.30 (s, 3H), 3.89 (br. s.,1H). LC-MS: m/z 452.1 (M+H)⁺.

Compound 224:5-(aminomethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General Procedure 3 by usingIntermediate 1 as methyl 2-(quinolin-6-yl) acetate in step A.

Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6 g,0.024 mol) and 3,4-diphenyl-1H-pyrazol-5-amine (5.64 g, 0.024 mol) wasdissolved in AcOH (300 ml). The mixture was warmed up to 95° C. for 4 h.After cooling to room temperature, the precipitate was filtered, washwith EtOAc, and dried under vacuum to get5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(10 g, 78% yield) as a yellow solid. LC-MS: m/z 535.2 (M+H)⁺.

Step C: To a solution of5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(10 g, 18.7 mmol) in DCM (100 ml) was added BCl₃ (25 ml, 25 mmol, 1.0Min DCM) at 0° C. The resultant mixture was stirred at 0° C. for 4 hours.The reaction was quenched with MeOH and concentrated. The residue wasstirred with sodium hydrogen carbonate solution and ethyl acetate for 30min. The solid was collected by filtration, wash with ethyl acetate, anddried under vacuum to get5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(8 g, 96% yield). LC-MS: m/z 445.1 (M+H)⁺.

Step D: To a suspension of5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(500 mg, 1.126 mmol) in DCM (3 ml) cooled in ice-bath was added SOCl₂(670 mg, 5.631 mmol) dropwise. The resultant mixture was then stirred atroom temperature overnight. The suspension was filtered, washed withethyl acetate, and dried under vacuum. The residue was purified byprep-TLC (DCM:MeOH=20:1) to get5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(300 mg). LC-MS: m/z 463.1 (M+H)⁺.

Step E: To a solution of5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(150 mg, 0.324 mmol) in DMF was added 7N NH₃ in methanol (15 ml) at 0°C. The reaction mixture was then warmed up to 40° C. for 65 hours in asealed tube to get the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.89 (dd, J=4.16, 1.75 Hz, 1H), 8.36 (d,J=7.52 Hz, 1H), 8.02 (d, J=8.87 Hz, 1H), 7.91 (s, 1H), 7.76-7.81 (m,1H), 7.52-7.62 (m, 5H), 7.34-7.40 (m, 3H), 7.29 (t, J=7.52 Hz, 2H), 7.15(d, J=7.25 Hz, 1H), 3.85 (br. s., 2H). LC-MS: m/z 444.8 (M+H)⁺.

Compound 225:3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General Procedure 3 (step B-C)by using Intermediate 2 as methyl4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate andIntermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine instep B.

Step B: methyl4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate(662 mg, 1.85 mmol) and4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (400 mg, 1.67 mmol)were dissolved in AcOH (10 ml). The resultant mixture was warmed up to100° C. for 16 h. The reaction was then cooled to room temperature,basified with saturated sodium hydrogen carbonate solution, andextracted with DCM (20 mL). The organic phase was washed with brine (20ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column (DCM:MeOH=30:1) to get5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(400 mg) as a white solid. LC-MS: m/z 546.2 (M+H)⁺.

Step C: To a suspension of5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(260 mg, 0.48 mmol) in DCM (5 ml) was added 1.0M BCl₃ in DCM (1.43 ml,1.43 mmol), the mixture was stirred at room temperature for 3 hours. Thereaction was quenched with saturated sodium hydrogen carbonate solutionand extracted with EtOAc (20 mL) to obtain the title compound.

¹H NMR (DMSO-d₆) δ: 11.21 (s, 1H), 7.78 (d, J=6.98 Hz, 1H), 7.38-7.49(m, 4H), 6.85-6.92 (m, 2H), 6.78-6.82 (m, 1H), 5.86 (br. s., 1H), 5.68(s, 1H), 4.77 (s, 1H), 4.33 (d, J=5.10 Hz, 2H), 4.29 (s, 3H), 2.22 (br.s., 2H), 2.06 (br. s., 2H), 1.70 (br. s., 4H). LC-MS: m/z 456.2 (M+H)⁺.

Compound 226:5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General Procedure 3, step E-F,starting from3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 225).

Step E: To a suspension of3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 225, 100 mg, 0.264 mmol) in DCM (3 ml) cooled in a ice-bathwas added SOCl₂ (52 mg, 0.0.44 mmol) dropwise. The resultant mixture wasstirred at room temperature for 3 hours. The reaction was quenched withsaturated sodium hydrogen carbonate solution and extracted with DCM (20mL). The organic phase was washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated invacuo. The residue waspurified by silica gel column (DCM:MeOH=40:1) to get5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(70 mg) as a yellow solid. LC-MS: m/z 474.2 (M+H)⁺.

Step F: A mixture of5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(70 mg, 0.148 mg) in 7N NH₃/MeOH (5 ml) in a sealed tube was stirred at100° C. overnight to get the title compound.

¹H NMR (DMSO-d₆) δ: 11.74 (br. s., 1H), 8.24 (br. s., 2H), 7.77 (d,J=7.32 Hz, 2H), 7.40-7.53 (m, 3H), 6.86-7.03 (m, 2H), 6.82 (d, J=8.24Hz, 1H), 5.92 (br. s., 1H), 4.30 (s, 4H), 3.94 (br. s., 2H), 2.23 (br.s., 2H), 2.05 (br. s., 2H), 1.70 (br. s., 4H). LC-MS: m/z 455.2 (M+H)⁺.

Compound 227

Step A:2-(benzyloxy)-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)acetamide

To a solution of Intermediate 1 (Compound 224, 100 mg, 0.226 mmol) andEt₃N (68.6 mg, 0.68 mmol) in DCM (3 ml) was added 2-(benzyloxy)acetylchloride (42 mg, 0.45 mmol) dropwise. The mixture was stirred for 2hours at ambient temperature. The reaction was quenched by addingsaturated sodium hydrogen carbonate solution and extracted with DCM (20mL). The combined organic layers were washed with brine (20 ml), driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by prep-TLC (DCM/MeOH=20/1) to obtain the Intermediate 2(40 mg, 30% yield).

Step B: Compound 227:2-hydroxy-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)acetamide

To a solution of Intermediate 2 (40 mg, 0.068 mmol) in DCM (1 ml) at 0°C. was carefully added 1M BBr₃ in DCM (3 ml, 3 mmol), the reactionmixture was stirred for 5 min at 0° C., and then warmed up to ambienttemperature for 1 hour. The reaction was quenched by careful addingMeOH. The resultant mixture was poured into saturated sodium hydrogencarbonate solution and extracted with EtOAc (3*20 ml). The combinedorganic layers were washed with saturated NaCl (20 ml), dried overNa₂SO₄, and concentrated in vacuo to give the title compound 3.

¹H NMR (DMSO-d₆) δ: 11.94 (s, 1H), 8.95 (d, J=2.69 Hz, 1H), 8.38 (d,J=7.25 Hz, 1H), 8.07 (d, J=8.60 Hz, 1H), 7.98 (s, 1H), 7.76 (dd, J=8.60,1.88 Hz, 1H), 7.59 (dd, J=8.33, 4.30 Hz, 1H), 7.42-7.53 (m, 5H),7.32-7.41 (m, 5H), 5.59 (br. s., 1H), 4.25 (br. s., 2H), 3.77 (d, J=5.37Hz, 2H), LC-MS: m/z 502.8 (M+H)⁺.

Compound 228:N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)acetamide

This compound was prepared according to Compound 227 (step A) by usingIntermediate 4 as acetyl chloride in step A.

To a solution of5-(aminomethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 224, 100 mg, 0.226 mmol) and DIPEA (87.3 mg, 0.68 mmol) in DCM(3 ml) was added acetyl chloride (21.24 mg, 0.271 mmol) dropwise. Afteraddition, the mixture was stirred for 2 hours at ambient temperature.The mixture was concentrated. The residue was basified with saturatedsodium hydrogen carbonate solution and extracted with DCM (20 mL). Thecombined organic layers were washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated in vacuo to obtain the titlecompound.

¹H NMR (DMSO-d₆) δ: 8.90 (br. s., 1H), 8.35 (d, J=8.87 Hz, 1H), 8.16 (s,1H), 8.02 (d, J=8.60 Hz, 1H), 7.96 (br. s., 1H), 7.89 (br. s., 1H), 7.76(d, J=7.79 Hz, 1H), 7.50-7.56 (m, 5H), 7.29-7.39 (m, 5H), 7.20 (d,J=6.98 Hz, 1H), 4.07 (br. s., 2H), 1.82 (s, 3H). LC-MS: m/z 485.9(M+H)⁺.

Compound 229:3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3, step B-C,by using Intermediate 8 as4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate (597 mg,1.67 mmol) and 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (400mg, 1.67 mmol) were dissolved in AcOH (10 ml). The mixture was stirredat 100° C. for 4 h. After cooling to room temperature, the solids werecollected by filtration, wash with EtOAc, and dried under vacuum to give5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 23% yield) as a white solid. LC-MS: m/z 513.9 (M+H)⁺.

Step C: To a solution of5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.1 mmol) in MeOH (5 ml) was added Pd/C (50 mg) and HCl (3drops). The mixture was stirred at rt under H₂ overnight. The reactionwas filtered and concentrated. The residue was mixed with sodiumhydrogen carbonate solution and ethyl acetate with stirring for 30 minto give the title compound.

¹H NMR (DMSO-d₆) δ: 11.27 (br. s., 1H), 7.64-7.91 (m, 2H), 7.35-7.62 (m,4H), 7.22-7.35 (m, J=8.6 Hz, 2H), 6.90-7.02 (m, J=8.9 Hz, 2H), 5.87 (br.s., 1H), 5.75 (br. s., 1H), 4.26-4.45 (m, 2H), 3.81 (s, 3H), 2.22 (br.s., 2H), 1.98-2.11 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z 428.3 (M+H)⁺.

Compound 230:3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3 (step A-C)by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetate in step A andIntermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine instep B.

Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (730 mg,2.01 mmol) and 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (500mg, 2.1 mmmol) were dissolved in AcOH (15 ml). The mixture was warmed upto 100′C for 16 h. After cooling to room temperature, the solids werecollected by filtration, wash with EtOAc, and dried under vacuum to give5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (700 mg, 65% yield) as a white solid.LC-MS: m/z 538.9 (M+H)⁺.

Step C: To a solution of5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (700 mg, 1.3 mmol) in DCM was addedBCl₃ (1.0M in DCM, 2.2 ml, 2.2 mmol) at 0° C. The mixture was stirred at0° C. for 2 hours. The reaction was quenched by careful adding MeOH andconcentrated. The residue was mixed with sodium hydrogen carbonatesolution and ethyl acetate with stirring for 30 min give the titlecompound.

¹H NMR (DMSO-d₆) δ: 8.87-8.96 (m, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.03 (d,J=8.6 Hz, 1H), 7.94 (s, 1H), 7.73-7.82 (m, 3H), 7.55 (dd, J=8.3, 4.3 Hz,1H), 7.43-7.51 (m, 2H), 7.40 (d, J=7.3 Hz, 1H), 5.82 (br. s., 1H), 4.35(s, 2H), 2.19 (br. s., 4H), 1.70 (br. s., 4H). LC-MS: m/z 449.3 (M+H)⁺.

Compound 231:3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3 (step A-C)by using Intermediate 1 as methyl 2-(quinoxalin-6-yl)acetate in step Aand Intermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-aminein step B.

Step C: To the solution of5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(170 mg, 0.32 mmol) in DCM (8 mL) cooled to 0° C. was added BCl₃ (1.5mL, 1.0 M in DCM) dropwise. Then the mixture was stirred at 0° C. for 2hours. The reaction was quenched by carefully adding saturated NaHCO₃(8mL), diluted with DCM (80 mL), washed with brine, dried over anhydroussodium sulfate and concentrated to obtain3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.57 (br. s., 1H), 8.99 (s, 2H), 8.07-8.22 (m, 2H),7.89 (dd, J=8.5, 1.8 Hz, 1H), 7.73-7.84 (m, 2H), 7.38-7.58 (m, 3H), 5.90(br. s., 1H), 5.77 (br. s., 1H), 4.42 (d, J=3.4 Hz, 2H), 2.23 (br. s.,2H), 2.09 (s, 2H), 1.72 (br. s., 4H). LC-MS: m/z 450.3 (M+H)⁺.

Compound 232:5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3, step D-E,starting from3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 229).

Step D: To a suspension of3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 229, 140 mg, 0.32 mol) in DCM (10 ml) was added SOCl₂ dropwise(386 mg, 3.2 mmol) at −20° C. The mixture was stirred at −20° C. for 1hour until SM was consumed. Then the reaction was quenched by addingMeOH at −20° C. The mixture was concentrated and purified by silica gelchromatography (DMC:MeOH=50:1) to a5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.74-7.83 (m, 2H), 7.37-7.53 (m, 3H), 7.25-7.32 (m,2H), 6.95-7.03 (m, 2H), 5.87 (br. s., 1H), 5.76 (s, 1H), 4.33 (br. s.,2H), 3.81 (s, 3H), 2.22 (br. s., 2H), 2.07 (br. s., 2H), 1.70 (br. s.,4H). LC-MS: m/z 446.3 (M+H)⁺.

Step E: A suspension of5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.11 mmol) and KI (18 mg, 0.11 mmol) in NH₃ in MeOH (7M, 10 mL)was stirred at 80° C. for 1 h under microwave irradiation to get thetitle compound.

¹H NMR (DMSO-d₆) δ: 7.71 (d, J=7.3 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.32(br. s., 1H), 7.15-7.24 (m, J=8.6 Hz, 2H), 6.93-7.00 (m, J=8.6 Hz, 2H),5.68 (br. s., 1H), 3.80 (s, 3H), 2.36 (br. s., 2H), 2.11 (d, J=3.0 Hz,2H), 1.58-1.79 (m, 4H). LC-MS: m/z 427.4 (M+H)⁺.

Compound 233:5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3, step D-E,starting from3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 230)

Step D: To a suspension of3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 230, 160 mg, 0.357 mol) in DCM (5 ml) was added SOCl₂ (1 ml)with a funnel. The mixture was stirred at room temperature for 1 hour.The precipitates were filtered, washed with ethyl acetate, and driedunder vacuum to give5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(170 mg) as a off-white solid which was directly used to the next stepwithout further purification. LC-MS: m/z 466.9 (M+H)⁺

Step E: A mixture of5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(80 mg, 0.171 mol) and NH₃ (7.0M in MeOH, 10 ml, 70 mol) in autoclavewas stirred at 40° C. for 2 days. The mixture was concentrated in vacuo.The residue was washed with water to afford the title compound.

¹H NMR (DMSO-d₆) δ: 8.84-8.93 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.01 (d,J=8.6 Hz, 1H), 7.87 (s, 1H), 7.68-7.78 (m, 3H), 7.52-7.58 (m, 1H),7.28-7.47 (m, 3H), 5.71 (br. s., 1H), 3.85 (s, 2H), 2.39 (br. s., 2H),2.11 (br. s., 2H), 1.57-1.79 (m, 4H). LC-MS: m/z 448.5 (M+H)⁺.

Compound 234:5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 3, step D-E,starting from3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 231).

Step D: To the solution of3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 231, 100 mg, 0.22 mmol) and DMF (1 drop, cat.) in DCM wasadded Thionyl chloride (0.2 mL) dropwise at 0° C. After addition, themixture was continued to stir at 0° C. for 1 hour. The reaction wasdiluted with DCM (60 mL), washed with saturated NaHCO₃(15 mL) and brine(20 mL), dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by prep-TLC (DCM:MeOH: 25:1) to obtain5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(90 mg) as yellow solid. LC-MS: m/z 468.3 (M+H)⁺.

Step E: The solution of5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(85 mg, 0.18 mmol) in NH₃ (4 mL, 7.0M in MeOH) was stirred at 40° C. ina sealed tube for 12 hours. After cooling to room temperature, themixture was filtered off to obtain5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 8.92 (dd, J=7.0, 1.9 Hz, 2H), 8.07 (d, J=8.6 Hz,1H), 8.01 (d, J=1.9 Hz, 1H), 7.91 (dd, J=8.9, 1.9 Hz, 1H), 7.73 (d,J=7.0 Hz, 2H), 7.42 (t, J=7.5 Hz, 2H), 7.33 (t, J=7.4 Hz, 2H), 5.69 (br.s., 1H), 3.88 (s, 2H), 2.40 (br. s., 2H), 2.12 (br. s., 2H), 1.60-1.78(m, 4H). LC-MS: m/z 449.3 (M+H)⁺.

Compound 235:1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)urea

Intermediate 1 was prepared according to General procedure 3 (step A-D)by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetate.

Step A: NaH (60% dispersion in mineral oil, 28.6 mg, 0.7 mmol) was addedin portions to the solution of urea (41.0 mg, 0.6 mmol) in DMF (10 mL)cooled to 0° C. and stirred at this temperature for 20 min.5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.2 mmol) was then added and stirred at 80° C. for 10 h. Aftercooling to room temperature, water was added, and the precipitate wasfiltered to get1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)urea.

¹H NMR (DMSO-d₆) δ: 8.89 (br. s., 1H), 8.36 (d, J=7.8 Hz, 1H), 8.02 (d,J=8.9 Hz, 1H), 7.89 (br. s., 1H), 7.77 (d, J=7.5 Hz, 1H), 7.44-7.59 (m,6H), 7.24-7.36 (m, 5H), 7.14 (d, J=6.7 Hz, 1H), 6.10 (br. s., 1H), 5.76(br. s., 2H), 4.02 (br. s., 2H). LC-MS: m/z 487.2 (M+H)⁺.

General Procedure 4

Step A: Compound 236:5-(aminomethyl)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 1 (Compound 222, 100 mg, 0.237 mmol) in 1ml DCM was carefully added 5 ml BBr₃ (1.0M in DCM, 5 mmol) at 0° C. Themixture was stirred at 0° C. for 2 hours. The reaction was quenched bycareful adding ice water at 0° C. The precipitated solids were filteredto give the title compound 2.

¹H NMR (DMSO-d₆) δ: 7.49-7.59 (m, 4H), 7.32-7.38 (m, 3H), 7.26 (t,J=7.52 Hz, 2H), 7.06-7.14 (m, 3H), 6.79 (d, J=8.33 Hz, 2H), 3.73 (s,2H). LC-MS: m/z 409.0 (M+H)⁺.

Compound 237:6-(4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 4 by usingIntermediate 1 as6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 209) in step A.

A mixture of6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 209, 60 mg, 0.147 mmol) and BBr₃ (1M in dichloromethane, 5 mL)was stirred at room temperature for 3 h. The mixture was quenched withmethanol at 0° C., and then evaporated to dryness to afford6-(4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.84 (s, 1H), 9.46 (s, 1H), 7.37-7.58 (m, 5H),7.25-7.37 (m, 5H), 7.12 (d, J=8.60 Hz, 2H), 6.82 (d, J=8.60 Hz, 2H),2.17 (s, 3H). LC-MS: m/z 394.1 (M+H)⁺.

Compound 238:6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

Step A: methyl 2-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate

To a solution of methyl 2-(3-fluoro-4-methoxyphenyl)acetate (1 g, 5.0mmol) in THF (15 ml) was added slowly LDA (2.5 ml, 2 mmol/ml in THF) at−30° C. Then acetyl chloride (500 mg, 6.5 mmol) was added slowly. Thereaction mixture was stirred for 30 mins at −30° C. and allowed to roomtemperature for 1 h. The mixture was poured into water, extracted overethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentratedto give the crude product (400 mg) as a yellow liquid, which was useddirectly to the next step without further purification.

Step B:6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl 2-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate (crude,400 mg) and 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH(10 ml) was heated to 120° C. overnight. The reaction mixture was cooledto room temperature. The precipitate was filtered off to give thedesired product6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 57% yield).

¹H NMR (DMSO-d₆) δ: 12.04 (s, 1H), 7.39-7.51 (m, 5H), 7.24-7.38 (m, 6H),6.94 (dd, J=11.7, 2.6 Hz, 1H), 6.88 (dd, J=8.5, 2.6 Hz, 1H), 3.83 (s,3H), 2.16 (s, 3H). LC-MS: m/z 426.2 (M+H)⁺.

Step C: Compound 238:6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.47 mmol) in CH₂Cl₂ (20 ml) was added slowly BBr₃ (1 ml, 1mmol/ml in CH₂Cl₂). And then the reaction mixture was stirred overnight.The mixture was adjusted to pH=7 with saturated NaHCO₃ solution. Theprecipitate was filtered off to give the desired product6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 9.57 (s, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 2H),7.44-7.50 (m, 2H), 7.29-7.38 (m, 3H), 7.26 (t, J=7.7 Hz, 2H), 7.06-7.14(m, 1H), 7.02 (dd, J=12.8, 1.7 Hz, 1H), 6.85-6.96 (m, 2H), 2.11 (s, 3H).LC-MS: m/z 411.9 (M+H)⁺.

Compound 239:6-(3-chloro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to Compound 238, step A-C, startingfrom methyl 2-(3-chloro-4-methoxyphenyl)acetate.

Step A: To a solution of methyl 2-(3-chloro-4-methoxyphenyl)acetate (2g, 9.346 mmol) in THF (20 ml) was added LDA (1.5 M in THF, 8.1 mL, 12.15mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 30min., and acetyl chloride (822 mg, 10.28 mmol) was added dropwise. Thenthe mixture was stirred at rt for 2 hours. The mixture was poured slowlyinto saturated NH₄Cl and extracted with EA (3×30 mL). The combinedorganic phase was washed with brine, dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was purified by silica gel column(PE:EA=0-30%) to get methyl 2-(3-chloro-4-methoxyphenyl)-3-oxobutanoate(500 mg) as a yellow oil. LC-MS: m/z 257.1 (M+H)⁺.

Step B: A suspension of methyl2-(3-chloro-4-methoxyphenyl)-3-oxobutanoate (200 mg, 0.850 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (261 mg, 1.020 mmol) in 1,4-dioxane (5ml) and AcOH (1 ml) was refluxed for 16 hours under N₂ protection. Thesolution was cooled to room temperature, concentrated, basified withsaturated sodium hydrogen carbonate solution to adjust pH equal to 7,and filtered. The filter cake was purified by prep-TLC (DCM:MeOH=20:1)to get 6-(3-chloro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg) as a white solid. LC-MS: m/z442.1 (M+H)⁺.

Step C: To a solution of6-(3-chloro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.113 mmol) in DCM (1 ml) was added 1.0M BBr₃ in DCM (3 ml, 3mmol) dropwise. The mixture was stirred for 2 hours at ambienttemperature. The reaction mixture was quenched by adding saturatedsodium hydrogen carbonate solution and extracted with DCM (20 ml). Thecombined organic layers were washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated in vacuo to obtain the titlecompound.

¹H NMR (DMSO-d₆) δ: 11.94 (br. s., 1H), 10.24 (s, 1H), 7.40-7.47 (m,4H), 7.38 (d, J=7.25 Hz, 1H), 7.34 (d, J=5.10 Hz, 4H), 7.29 (d, J=1.88Hz, 1H), 7.07-7.12 (m, 1H), 7.00-7.05 (m, 1H), 2.18 (s, 3H). LC-MS: m/z428.1 (M+H)⁺.

Compound 240:3-(cyclohex-1-en-1-yl)-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 4 by usingIntermediate 1 as3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 212) in step A.

To a solution of3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 212, 50 mg, 0.118 mmol) in DCM (1 ml) was added 1.0 M BBr₃ inDCM (3 ml, 3 mmol) dropwise at 0° C. The mixture was stirred for 3 hoursat ambient temperature. The reaction was quenched with ice water at −10°C. and concentrated to obtain the title compound.

¹H NMR (DMSO-d₆) δ: 7.76 (d, J=7.02 Hz, 2H), 7.30-7.52 (m, 3H), 7.09 (m,J=7.93 Hz, 2H), 6.82 (m, J=7.93 Hz, 2H), 5.83 (br. s., 1H), 2.21 (br.s., 3H), 2.18 (br. s., 2H), 2.03 (br. s., 2H), 1.67 (br. s., 4H). LC-MS:m/z 398.0 (M+H)⁺.

Compound 241:5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-hydroxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

This compound was prepared according to General procedure 4 by usingIntermediate 1 as5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 232) in step A.

To a solution of5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 232, 85 mg, 0.2 mmol) in DCM (1 ml) was added 1.0M BBr₃ in DCM(3 ml, 3 mmol) dropwise. The mixture were stirred for 3 hours at ambienttemperature, The reaction was quenched with ice water and concentratedto obtain the title compound.

¹H NMR (DMSO-d₆) δ: 8.21 (s, 1H), 7.69 (d, J=6.72 Hz, 2H), 7.37 (d,J=6.98 Hz, 2H), 7.31 (d, J=6.72 Hz, 1H), 7.06 (m, J=8.06 Hz, 2H), 6.77(m, J=8.33 Hz, 2H), 5.66 (br. s., 1H), 3.68 (br. s., 3H), 2.34 (br. s.,2H), 2.09 (br. s., 2H), 1.53-1.74 (m, 4H). LC-MS: m/z 413.2 (M+H)⁺.

Compound 242

Step A: 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (1 g, 8.536 mmol) in THF (20 ml)was added LiHMDS (2.0 M in THF, 5.1 mL, 10.2 mmol) dropwise at 0° C. Themixture was stirred at 0° C. for 30 min and warmed up to roomtemperature for 15 min. 4-methoxybenzoyl chloride (1.75 g, 10.24 mmol)was added dropwise at 0° C. Then the mixture was stirred at roomtemperature for 16 hours. The mixture was poured slowly into saturatedNH₄Cl and extracted with EA (3×10 mL). The combined organic phase waswashed with brine, dried over anhydrous MgSO₄ and concentrated in vacuoto get crude product (2.5 g) as a yellow oil. LC-MS: m/z 252.1 (M+H)⁺.

Step B: 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine

A suspension of 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile (2 g,8.761 mmol) and hydrazine hydrate (2.4 g, 43.804 mmol) in EtOH (10 ml)and AcOH (2 ml) was refluxed for 16 hours under N₂ protection. Thesolution was cooled to the room temperature and concentrated, basifiedwith sodium hydrogen carbonate solution to adjust pH equal to 7, andextracted with EtOAc. The combined organic layers were washed with brine(30 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue was purified by silica gel column (PE:EA=3:1) to get3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (700 mg) as a whitesolid.

¹H NMR (DMSO-d₆) δ 11.76-11.92 (m, 1H), 7.27-7.35 (m, 2H), 7.15-7.24 (m,5H), 6.88 (d, J=8.3 Hz, 2H), 4.33-4.63 (m, 2H), 3.74 (s, 3H). LC-MS: m/z266.1 (M+H)⁺.

Step C: Compound 243:2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (250 mg,0.942 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (458 mg, 1.885mmol) in 1,4-dioxane (10 ml) and AcOH (2 ml) was refluxed for 16 hoursunder N₂ protection. The solution was cooled to the room temperature andconcentrated, basified with saturated sodium hydrogen carbonate solutionto adjust pH equal to 7, and filtered to afford2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ12.01 (s, 1H), 8.94 (d, J=2.75 Hz, 1H), 8.40 (d,J=7.93 Hz, 1H), 8.08 (d, J=8.54 Hz, 1H), 7.93-7.99 (m, 1H), 7.75 (dd,J=8.70, 1.68 Hz, 1H), 7.58 (dd, J=8.24, 4.27 Hz, 1H), 7.41-7.51 (m, 3H),7.34-7.40 (m, 4H), 6.90 (d, J=8.55 Hz, 2H), 3.76 (s, 3H), 2.25 (s, 3H).LC-MS: m/z 459.2 (M+H)⁺.

Step D: Compound 242:2-(4-hydroxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.225 mmol) in DCM (1 ml) was added 1.0 M BBr₃ in DCM (3 ml, 3mmol) dropwise. The mixture was stirred for 2 hours at ambienttemperature. The reaction mixture was quenched by adding saturatedsodium hydrogen carbonate solution and extracted with DCM (20 mL). Thecombined organic layers were washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated in vacuo to obtain the titlecompound.

¹H NMR (DMSO-d₆) δ: 11.97 (br. s., 1H), 9.63 (s, 1H), 8.93 (d, J=2.69Hz, 1H), 8.39 (d, J=7.52 Hz, 1H), 8.07 (d, J=8.87 Hz, 1H), 7.95 (d,J=1.88 Hz, 1H), 7.75 (dd, J=8.60, 1.88 Hz, 1H), 7.57 (dd, J=8.33, 4.30Hz, 1H), 7.42-7.49 (m, 2H), 7.35-7.41 (m, 3H), 7.27 (m, J=8.60 Hz, 2H),6.71 (m, J=8.60 Hz, 2H), 2.24 (s, 3H). LC-MS: m/z 445.2 (M+H)⁺.

Compound 244

Step A: (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate

The solution of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) andDMF-DMA (4.0 mL) in DMF was stirred at 85° C. for 12 h. After cooling toroom temperature, the mixture was diluted with water, extracted withEtOAc, dried over Na₂SO₄, and concentrated to get the crude product (3.8g) which was directly used to the next step without furtherpurification. LC-MS: m/z 257.3 (M+H)⁺.

Step B: Compound 244:2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.9 mmol) and(E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1mmol) in AcOH (3 mL) was stirred at 100° C. for 2 h. After cooling toroom temperature, the solvent was removed by vacuum, saturated NaHCO₃(6mL) was added, and the precipitate was filtered. The filter cake waswashed with water (2 mL) and MeOH (2 mL) to afford2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H),8.37-8.47 (m, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.10-8.16 (m, 2H), 8.03-8.10(m, 1H), 7.56 (dd, J=8.3, 4.0 Hz, 1H), 7.45-7.54 (m, 4H), 7.32-7.45 (m,6H). LC-MS: m/z 415.3 (M+H)⁺.

Compound 245

Step A: ethyl 2-(3-cyano-4-nitrophenyl)-3-oxobutanoate

5-fluoro-2-nitrobenzonitrile (5 g, 30 mmol), ethyl 3-oxobutanoate (7.8g, 60 mmol) and K₂CO₃ (12.46 g, 90 mmol) in DMSO (50 mL) was stirred at50° C. for 16 h. The mixture was acidified with HCl (1M) to pH=7 andextracted with EA (50 mL×3). The organic layer was dried andconcentrated to give the crude which was purified by silica gelchromatography (PE:EA=3:1) to get Intermediate 2 (6.15 g, 77% yield).

¹H NMR (CHLOROFORM-d) δ: 8.33 (d, J=8.6 Hz, 1H), 7.75 (d, J=1.9 Hz, 1H),7.63 (dd, J=8.6, 1.9 Hz, 1H), 3.84 (s, 1H), 3.76 (s, 3H), 1.95 (s, 3H).LC-MS: m/z 277.2 (M+H)⁺.

Step B:5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-2-nitrobenzonitrile

A mixture of Intermediate 2 (3 g, 1.1 mmol),3,4-diphenyl-1H-pyrazol-5-amine (2.7 g, 1.1 mmol), and TsOH (200 mg, 1.1mmol) in toluene (20 mL) was stirred at 120° C. for 4 h. The mixture wascooled to r.t. and filtered to give the crude yellow solid which wasrecrystallized from MeOH to give the pure Intermediate 3 (2.5 g, 51%yield).

¹H NMR (DMSO-d₆) δ: 8.45 (d, J=8.6 Hz, 1H), 8.14-8.30 (m, 1H), 8.01 (d,J=8.6 Hz, 1H), 7.20-7.50 (m, 10H), 2.28 (s, 3H). LC-MS: m/z 448.1(M+H)⁺.

Step C:2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzonitrile

The Intermediate 3 (3 g, 0.7 mmol) and 10% Pd/C (300 mg) in DMF (10 mL)and MeOH (50 mL) was stirred at r.t. for 16 h under H₂ atmosphere. Themixture was filtered and concentrated in vacuo. The residue was purifiedby silica gel column (PE:EA=10:1-1:1) to give Intermediate 4 (1.8 g, 64%yield).

¹H NMR (DMSO-d₆) δ: 11.91 (s, 1H), 7.38-7.52 (m, 5H), 7.21-7.38 (m, 7H),6.85 (d, J=8.9 Hz, 1H), 6.16 (s, 2H), 2.20 (s, 3H). LC-MS: m/z 418.3(M+H)⁺.

Step D:2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde

The Intermediate 4 (800 mg, 1.9 mmol) in dry DCM (10 mL) was cooled to0° C. and DIBAL-H (19 mmol, 2M) was added dropwise. The mixture waswarmed up to r.t. for 16 h. The reaction was quenched with MeOH andconcentrated. The residue was purified by silica gel column (PE;EA=1:1)to get Intermediate 5 (150 mg, 19% yield).

¹H NMR (DMSO-d₆) δ: 11.90 (br. s., 1H), 9.85 (s, 1H), 7.38-7.51 (m, 6H),7.22-7.38 (m, 8H), 6.84 (d, J=8.6 Hz, 1H), 2.23 (s, 3H). LC-MS: m/z421.5 (M+H)⁺.

Step E: Compound 245:5-methyl-2,3-diphenyl-6-(quinazolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The Intermediate 5 (60 mg, 0.14 mmol) and formamidine (126 mg, 2.86mmol) in DMF was stirred at 160° C. for 2 h. The mixture wasconcentrated to get the title compound 6.

¹H NMR (DMSO-d₆) δ: 12.13 (br. s., 1H), 9.66 (s, 1H), 9.35 (s, 1H), 8.17(s, 1H), 8.08 (d, J=12.1 Hz, 1H), 7.95-8.05 (m, 1H), 7.41-7.52 (m, 6H),7.34-7.41 (m, 5H), 2.27 (s, 3H). LC-MS: m/z 430.2 (M+H)⁺.

Compound 246:6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)quinoline-2-carboxylic Acid

Step A:2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzalde-hyde(50 mg, 0.12 mmol), 2-oxopropanoic acid (52 mg, 0.6 mmol), and KOH (23mg, 0.6 mmol) in EtOH (5 mL) was stirred at r.t. for 16 h. The mixturewas acidified with 1 M HCl to pH=6 and extracted with DCM (10 ml×3). Theorganic layer was dried and concentrated to afford the desired product.

¹H NMR (DMSO-d₆) δ: 12.12 (br. s., 1H), 8.58 (d, J=8.3 Hz, 1H),8.15-8.24 (m, 2H), 8.09 (br. s., 1H), 7.87 (d, J=8.3 Hz, 1H), 7.42-7.50(m, 5H), 7.33-7.42 (m, 6H), 2.28 (s, 3H). LC-MS: m/z 473.5 (M+H)⁺.

Compound 247

Step A: 2-(5-fluoro-2-nitrophenyl)-1,3-dioxolane

To a solution of 5-fluoro-2-nitrobenzaldehyde (5.0 g, 29.6 mmol) intoluene (150 mL) was added ethylene glycol (2.75 g, 44.4 mmol) andp-TSOH (500 mg). After addition, the mixture was heated to refluxovernight. The reaction mixture was cooled to RT and diluted with EtOAc.The combined organic phase was washed with water and brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure togive Intermediate 2 (6.4 g) as a yellow oil which was directly used inthe next step without further purification. LC-MS: m/z 214.6 (M+H)⁺.

Step B: methyl 2-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)-3-oxobutanoate

To a mixture of Intermediate 2 (5.4 g, 25.4 mmol) in DMF (150 mL) wasadded methyl 3-oxobutanoate (4.42 g, 38.0 mmol, 1.5 eq) and K₂CO₃ (5.24g, 38.0 mmol, 1.5 eq) at RT. After addition, the mixture was heated to55° C. overnight. The reaction mixture was cooled to RT and diluted withEtOAc. The combined organic phase was washed with water and brine, driedover anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (EtOAc/PE=1/10) to afford the desired product Intermediate 3 (4.23g, 54% yield). LC-MS: m/z 309.9 (M+H)⁺.

Step C:6-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 3 (4.23 g, 13.7 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (3.22 g, 13.7 mmol, 1.0 eq) in CH₃COOH(200 mL) was stirred at 110° C. overnight, and then cooled to roomtemperature. The precipitate was collected by filtration and washed withEA to afford the desired product Intermediate 4 (4.01 g, yield 59%) as ayellow solid. LC-MS: m/z 494.9 (M+H)⁺.

Step D:2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde

To a solution of Intermediate 4 (1.0 g, 2.02 mmol) in a mixed solutionof MeOH (50 mL)/DCM (5 mL)/H₂O (5 mL) was added Pd/C (0.2 g) and HCOONH₄(673 mg, 10.1 mmol, 5.0 eq) at RT under N₂. After addition, the mixturewas heated to reflux overnight. The reaction mixture was cooled to roomtemperature, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to affordIntermediate 5 (610 mg, 72% yield). LC-MS: m/z 420.9 (M+H)⁺.

Step E: Compound 2476-(3-hydroxy-2-methylquinolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of Intermediate 5 (150 mg, 0.36 mmol) and1-hydroxypropan-2-one (52.9 mg, 0.71 mmol, 2.0 eq) in EtOH (5 mL) wasadded KOH (40.1 mg, 0.71 mmol, 2.0 eq) at RT. After addition, themixture was heated to reflux overnight. The reaction mixture wasconcentrated under reduced pressure to afford the title product.

¹H NMR (DMSO-d₆) δ: 12.00 (s, 1H), 10.32 (s, 1H), 7.85 (d, J=8.4 Hz,1H), 7.70 (d, J=2.0 Hz, 1H), 7.50-7.39 (m, 7H), 7.38-7.30 (m, 5H), 2.56(s, 3H), 2.22 (s, 3H). LC-MS: m/z 459.0 (M+H)⁺.

Compound 248

Step A: methyl3-((2-((4-methoxybenzyl)thio)-4-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)amino)-3-oxopropanoate

To a mixture of Intermediate 1 (50 mg, 0.09 mmol) and DIPEA (23.2 mg,0.18 mmol, 2.0 eq) in THF (5 mL) was added methyl3-chloro-3-oxopropanoate (24.5 mg, 0.18 mmol, 2.0 eq). The reactionmixture was then stirred at rt for 8 h. The mixture was partitionedbetween EA and H₂O. The organic phase was washed with water and brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to give crude Intermediate 2 (50 mg) which was directly used tothe next step without further purification. LC-MS: m/z 645.1 (M+H)⁺.

Step B: Compound 248:2-(6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzo[d]thiazol-2-yl)acetate

A mixture of Intermediate 2 (50 mg, 0.08 mmol) in TFA (3 mL) was stirredat 75° C. for 3 h. The mixture was concentrated under reduced pressureto afford the desired product 3.

¹H NMR (DMSO-d₆) δ: 12.01 (s, 1H), 7.44 (m, 6H), 7.34 (m, 5H), 4.37 (s,2H), 3.71 (s, 3H), 2.20 (s, 3H). LC-MS: m/z 507.0 (M+H)⁺.

Compound 249

Step A: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate

To a solution of methyl 2-(4-methoxyphenyl)acetate (3.0 g, 16.7 mmol) inTHF (10 mL) was added dropwise LDA (10 mL, 19.98 mmol, 1.2 eq) and HMPA(598 mg, 3.33 mmol, 0.2 eq) at −78° C. After addition, the mixture wasstirred at −48° C. for 0.5 h. The mixture was then cooled to −78° C.,2-(benzyloxy)acetyl chloride (3.69 g, 17 mmol) in dry THF (3 mL) wasadded slowly and stirred at RT overnight. The reaction was quenched withNH₄Cl solution, extracted with EA. The combined organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (EtOAc/PE=1/4) to afford Intermediate 2(2.7 g, 49% yield). LC-MS: m/z 329.1 (M+H)⁺.

Step B:5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 2 (2.7 g, 8.23 mmol) and compound 8 (1.3 g,8.23 mmol, 1.0 eq) in CH₃COOH (10 mL) was stirred at 100° C. for 3 h andthen cooled to room temperature. The mixture was concentrated underreduced pressure and washed with MeOH to afford the desired Intermediate3 (2.4 g, yield 67%) as a white solid. LC-MS: m/z 437.9 (M+H)⁺.

Step C:5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of Intermediate 3 (2.4 g, 5.49 mmol, 1 eq.) and Cs₂CO₃(2.14 g, 6.59 mmol, 1.2 eq.), in DMF (8 ml) was added MeI (774 mg, 5.49mmol, 1.0 eq). The mixture was then stirred at rt overnight. The mixturewas poured into water (100 ml) and filtered. The filter cake was washedwith MeOH to give Intermediate 4 (2.9 g) as a white solid. LC-MS: m/z451.9 (M+H)⁺.

Step D:5-((benzyloxy)methyl)-3-bromo-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of Intermediate 4 (2.9 g, 6.6 mmol, 1 eq) in DMF (20 ml)was added NBS (1.37 g, 7.94 mmol, 1.2 eq). The reaction mixture was thenstirred at rt for 2 h. The mixture was poured into water (200 ml) andfiltered to give Intermediate 5 (3.1 g, yield 91%) as a white solid.LC-MS: m/z 430.1 (M+H)⁺.

Step E:5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (1.5 g, 2.83 mmol), phenylboronic acid(414 mg, 3.40 mmol, 1.2 eq), Pd₁₁₈ (368 mg, 0.57 mmol, 0.2 eq) and K₂CO₃(982 mg, 7.1 mmol, 2.5 eq) in 1.4-dioxane (30 ml) and H₂O (1.5 ml) wasstirred at 90° C. for 5 h under N₂ atmosphere. The reaction mixture wasthen cooled to r.t. and filtered. The filtrate was concentrated in vacuoand purified by flash column chromatography silica gel to obtainIntermediate 6 (300 mg, 20% yield). LC-MS: m/z 527.9 (M+H)⁺

Step F: Compound 249:5-(hydroxymethyl)-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 6 (150 mg, 0.28 mmol) in dry DCM (5 mL)was added dropwise BCl₃/DCM (5 mL, 1N, 2.0 eq) at 0° C. After addition,the mixture was stirred at rt for 2 h. The mixture was quenched bycareful adding ice-water and extracted with EA. The combined organicphase was washed with water and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give the titlecompound 7.

¹H NMR (DMSO-d₆) δ: 7.42-7.50 (m, 5H), 7.34-7.40 (m, 2H), 7.22-7.32 (m,5H), 6.98-7.07 (m, 2H), 5.63 (t, J=4.8 Hz, 1H), 4.34 (d, J=4.8 Hz, 2H),3.82 (s, 3H), 3.44 (s, 3H). LC-MS: m/z 438.0 (M+H)⁺.

Compound 250

Step A: 3-(4-nitrophenyl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (585 mg, 5 mmol) in THF (30 mL)was added n-BuLi (2.5 mol/L, 2 mL, 1.0 eq.) at −78° C. 4-nitrobenzoylchloride (1.1 eq) was added dropwise after the mixture was stirred at−78° C. for 30 min. The mixture was stirred at −78° C. for 15 min, andthen warmed to r.t. and stirred for 3 h. The mixture was diluted with EA(30 mL) and quenched with saturated NH₄Cl. The organic phase wasseparated and washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to get Intermediate 2 which was used to the nextstep without further purification. LC-MS: m/z 267.0 (M+H)⁺.

Step B: 3-(4-nitrophenyl)-4-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 2 (750 mg, 2.8 mmol, 1 eq.) and hydrazinehydrate (2 eq.) in EtOH/AcOH (5/1.10 mL/2 mL) was refluxed for 2 h. Themixture was then cooled to r.t. and evaporated. The residue wasdissolved in EA (10 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the water phase was extracted with EA (10 mL*3).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by prep-TLCto afford the desired Intermediate 3 as a bright yellow solid. LC-MS:m/z 281.1 (M+H)⁺.

Step C: Compound 251:5-methyl-2-(4-nitrophenyl)-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (95 mg, 0.34 mmol, 1 eq.) and methyl3-oxo-2-(quinolin-6-yl)butanoate 7 (1.5 eq.) in AcOH (5 mL) was stirredat 100° C. for 1 h. Then the mixture was cooled to r.t. and evaporated.The residue was dissolved in EA (5 mL) and neutralized with 10% NaHCO₃.The organic phase was separated and the water phase was extracted withEA (5 mL*3). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by prep-TLC to afford Intermediate 4.

¹H NMR (DMSO-d₆) δ: 12.19 (br. s., 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H),8.40 (d, J=7.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.6 Hz, 1H),7.97 (d, J=1.6 Hz, 1H), 7.75 (dd, J=8.6, 1.8 Hz, 1H), 7.70 (d, J=8.8 Hz,2H), 7.58 (dd, J=8.4, 4.4 Hz, 1H), 7.46-7.54 (m, 3H), 7.36-7.42 (m, 2H),2.26 (s, 3H). LC-MS: m/z 474.0 (M+H)⁺

Step D: Compound 250:2-(4-aminophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 4 (35 mg, 0.07 mmol) in THF (10 mL) wasadded saturated NH₄Cl (1 mL) and zinc powder (96 mg, 1.5 mmol, 20 eq.).The reaction was stirred at r.t. for 5 h. LCMS indicated that thereaction was completed. The mixture was filtered through celite. Thefiltrate was extracted with DCM (5 mL*3). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuoto afford the desired product compound 5.

¹H NMR (DMSO-d₆) δ: 8.82-8.94 (m, 1H), 8.22-8.43 (m, 3H), 8.00 (d, J=8.6Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.2, 4.2 Hz,1H), 7.47 (d, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 2H), 7.20 (d, J=7.2 Hz,1H), 7.15 (d, J=8.2 Hz, 2H), 6.49 (d, J=8.2 Hz, 2H), 2.19 (s, 3H).LC-MS: m/z 444.9 (M+H)⁺.

Compound 252

Step A: methyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate

To a solution of methyl 1H-pyrrole-3-carboxylate (2 g, 16.0 mmol) in THF(80 mL) was added sodium hydride (768 mg, 60% content, 19.2 mmol, 1.2eq.) at 0° C. (2-(chloromethoxy)ethyl)trimethylsilane (4.0 g, 24 mmol,1.5 eq.) was added dropwise after the mixture was stirred at 0° C. for30 min. Then the mixture was stirred at r.t. overnight. The mixture wasdiluted with EA (80 mL) and quenched with saturated NH₄Cl. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by flashchromatography to afford the desired product 2 as a colorless oil. (2.1g, 51% yield)

¹H NMR (CHLOROFORM-d) δ: 7.40 (t, J=2.0 Hz, 1H), 6.72-6.75 (m, 1H), 6.62(dd, J=3.0, 1.6 Hz, 1H), 5.19 (s, 2H), 3.82 (s, 3H), 3.45 (dd, J=8.8,7.8 Hz, 2H), 0.86-0.93 (m, 2H), −0.02 (s, 9H). LC-MS: m/z 256.0 (M+H)⁺

Step B:3-oxo-2-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)propanenitrile

To the mixture of Intermediate 2 (2.1 g, 8.2 mmol) and2-phenylacetonitrile (1.16 g, 9.9 mmol, 1.2 eq.) in THF (80 mL) wasadded NaHMDS (2 mol/L in THF, 4.9 mL, 1.2 eq.) dropwise at 0° C. Themixture was then stirred at r.t. overnight. The mixture was diluted withEA (80 mL) and quenched with saturated NH₄Cl. The organic phase wasseparated and washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyto afford the desired product 3 as a light yellow solid (2 g, 71%yield).

¹H NMR (CHLOROFORM-d) δ: 7.45-7.50 (m, 3H), 7.35-7.42 (m, 3H), 6.76 (dd,J=3.0, 2.2 Hz, 1H), 6.66 (dd, J=3.0, 1.8 Hz, 1H), 5.21 (s, 1H), 5.18 (s,2H), 3.40-3.47 (m, 2H), 0.85-0.92 (m, 2H), −0.03 (s, 9H). LC-MS: m/z341.2 (M+H)⁺

Step C:4-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)-1H-pyrazol-5-amine

The mixture of Intermediate 3 (2 g, 5.9 mmol, 1 eq.) and hydrazinehydrate (590 mg, 11.8 mmol, 2 eq.) in EtOH/AcOH (5/1, 40 mL/8 mL) wasrefluxed for 2 h. Then the mixture was cooled to r.t. and evaporated.The residue was dissolved in EA (40 mL) and neutralized with 10% NaHCO₃.The organic phase was separated and the the water phase was extractedwith EA (10 mL*3). The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography to afford the desired Intermediate 4 asa yellow solid. (2 g, 99% yield)

¹H NMR (CHLOROFORM-d) δ: 7.37-7.42 (m, 4H), 7.28-7.31 (m, 1H), 6.77 (t,J=1.8 Hz, 1H), 6.72 (t, J=2.4 Hz, 1H), 6.20 (dd, J=2.8, 1.8 Hz, 1H),5.10 (s, 2H), 3.37-3.44 (m, 2H), 0.83-0.90 (m, 2H), −0.05-−0.01 (m, 9H).LC-MS: m/z 355.3 (M+H)⁺

Step D:5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 4 (500 mg, 1.4 mmol, 1 eq.) and methyl3-oxo-2-(quinolin-6-yl)butanoate 9 (1.5 eq.) in AcOH (10 mL) was stirredat 100° C. for 1 h. Then the mixture was cooled to r.t. and evaporated.The residue was dissolved in EA (5 mL) and neutralized with 10% NaHCO₃.The organic phase was separated and the water phase was extracted withEA (5 mL*3). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (DCM/Methanol=10/1, silica gel, uv) toget Intermediate 5 (550 mg, 71% yield). LC-MS: m/z 548.4 (M+H)⁺

Step E:2-(1-(hydroxymethyl)-1H-pyrrol-3-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]-pyrimidin-7(4H)-one

To a solution of Intermediate 5 (550 mg, 1.0 mmol) in DCM (15 mL) wasadded trifluoroacetic acid (1.5 mL). The mixture was stirred at r.t.overnight. The mixture was concentrated in vacuo to get Intermediate 6which was used to the next step without further purification. (450 mg).LC-MS: m/z 448.2 (M+H)⁺

Step F: Compound 252:5-methyl-3-phenyl-2-(1H-pyrrol-3-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 6 (450 mg, 1.0 mmol) in THF (15 mL) wasadded aq. NaOH solution (6 mol/L, 3 mL). The mixture was stirred at r.t.for 2 h to give the desired product 7.

¹H NMR (DMSO-d₆) δ: 10.78 (br. s., 1H), 8.74-8.91 (m, 1H), 8.32 (d,J=8.4 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.6 Hz,1H), 7.58 (d, J=7.4 Hz, 2H), 7.49 (dd, J=8.2, 4.4 Hz, 1H), 7.34 (t,J=7.4 Hz, 2H), 7.14-7.24 (m, 1H), 6.97 (br. s., 1H), 6.68 (br. s., 1H),6.24 (br. s., 1H), 2.16 (s, 3H). LC-MS: m/z 418.0 (M+H)⁺.

Compound 253

Step A: ethyl 2-(3-chloro-4-nitrophenyl)-3-oxobutanoate

To a mixture of 2-chloro-4-fluoro-1-nitrobenzene (10.0 g, 57.1 mmol) andCs₂CO₃ (22.3 g, 68.5 mmol, 1.2 eq) in DMF (100 mL) was added ethyl3-oxobutanoate (7.42 g, 57.1 mmol, 1.0 eq). Then the reaction mixturewas stirred at 60° C. for 5 h. The mixture was partitioned between EAand H₂O. The combined organic phase was washed with water and brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (EtOAc/PE=1/10) to afford the desired Intermediate 2 (9.0 g, 55%yield). LC-MS: m/z 285.9 (M+H)⁺.

Step B:6-(3-chloro-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 2 (7.6 g, 26.7 mmol) and compound 9 (6.27 g,26.7 mmol, 1.0 eq) in CH₃COOH (30 mL) was stirred at 100° C. for 5 h.The reaction was then cooled to room temperature. The mixture wasfiltered and the filter cake was washed with MeOH to afford the desiredIntermediate 3 (8.9 g, yield 73%) as a white solid. LC-MS: m/z 456.9(M+H)⁺.

Step C:6-(3-((4-methoxybenzyl)thio)-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 3 (8.0 g, 17.5 mmol), K₂CO₃ (6.1 g, 43.75mmol, 2.5 eq) and (4-methoxyphenyl)methanethiol (5.4 g, 35.08 mmol, 1.0eq) in DMF (35 mL) was stirred at 110° C. overnight. The mixture waspartitioned between EA and H₂O. The combined organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to afford the desired Intermediate 4 (8.2g, 81% yield). LC-MS: m/z 574.9 (M+H)⁺.

Step D:6-(4-amino-3-((4-methoxybenzyl)thio)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To Intermediate 4 (1.0 g, 1.74 mmol, 1 eq.) in methanol (50 ml) and THF(60 ml) was added Pd/C (30 mg). The mixture was stirred rt under H₂atmosphere overnight. The mixture was filtered through a celite pad, andthe filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to afford the desired Intermediate 5(700 mg, 74% yield). LC-MS: m/z 544.9 (M+H)⁺.

Step E:2-(1,3-dioxoisoindolin-2-yl)-N-(2-((4-methoxybenzyl)thio)-4-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide

To a mixture of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (452 mg, 2.20mmol) in DCM (5 mL) was added oxalyl chloride (3 ml) and cat. DMF (1.0drop) at 0° C. Then the reaction mixture was stirred at rt for 4 h. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in DCM (2 ml) and added to a solution of Intermediate 5(300 mg, 0.55 mmol) in DCM (5 ml) dropwise at 0° C. under N₂ atmosphere.The mixture was stirred rt overnight. The mixture was concentrated invacuo. The residue was purified by column chromatography on silica gel(EtOAc/PE=1/5) to afford Intermediate 6 (250 mg, 62% yield). LC-MS: m/z731.9 (M+H)⁺.

Step F:2-((6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzo[d]thiazol-2-yl)methyl)isoindoline-1,3-dione

A mixture of Intermediate 6 (250 mg, 0.34 mmol) in TFA (5 mL) wasstirred at 75° C. for 3 h. The mixture was concentrated under reducedpressure. The residue was washed with MeOH to afford the desiredIntermediate 7 (220 mg, 94% yield). LC-MS: m/z 593.9 (M+H)⁺.

Step G: Compound 253:6-(2-(aminomethyl)benzo[d]thiazol-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of Intermediate 7 (200 mg, 0.33 mmol) in EtOH (8 mL) wasadded N₂H₄—H₂O (2 ml). Then the reaction mixture was stirred at rt for 3h. The mixture was partitioned between EA and H₂O. The combined organicphase was washed with water and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to afford the titleCompound 8.

¹H NMR (DMSO-d₆) δ: 8.18 (s, 1H), 8.01 (s, 1H), 7.94 (d, J=8.4 Hz, 1H),7.36-7.52 (m, 7H), 7.33 (m, 4H), 4.26 (s, 2H), 2.18 (s, 3H). LC-MS: m/z464.1 (M+H)⁺.

Compound 254

Step A: methyl 2-(4-fluoro-3-nitrophenyl) acetate

To a solution of 2-(4-fluoro-3-nitrophenyl) acetic acid (4.5 g, 22.6mmol) in 50 mL of methanol was added 1 mL of conc. sulfuric acid at 0°C. The resulting mixture was then heated to reflux overnight. Themixture was concentrated in vacuo to 10 mL and quenched with aqueoussodium bicarbonate to pH 7. The resultant mixture was extracted withethyl acetate (30 mL*3). The organic phase was washed with brine, driedover sodium sulfate and evaporated in vacuo to afford methyl2-(4-fluoro-3-nitrophenyl) acetate (4.1 g, 85% yield) as a yellow solidwhich was used for next step without further purification.

1H NMR (Chloroform-d) δ: 8.02 (dd, J=6.98 Hz, 2.15 Hz, 1H), 7.59 (ddd,J=8.60 Hz, 4.03 Hz, 2.42 Hz, 1H), 7.21-7.38 (m, 1H), 3.75 (s, 3H), 3.71(s, 2H), 19F NMR (Chloroform-d) δ-: 119.68 (s, 1F).

Step B: methyl 2-(4-(2-methoxy-2-oxoethyl)-2-nitrophenyl-amino) acetate

A mixture of methyl 2-(4-fluoro-3-nitrophenyl) acetate (4.1 g, 19.2mmol), methyl 2-aminoacetate hydrochloride (2.67 g, 21.2 mmol), and N,N-diisopropylethylamine (5.4 g, 42.2 mmol) in N,N-dimethylformamide (50mL) was heated to 30° C. overnight. The mixture was diluted with brine(100 mL) and extracted with ethyl acetate (30 mL*3). The combinedorganic phase was washed with brine, dried over sodium sulfate andevaporated in vacuo to afford methyl2-(4-(2-methoxy-2-oxoethyl)-2-nitrophenyl-amino) acetate (4.6 g, 85%yield) as yellow solid which was used for next steps without furtherpurification. LC-MS: m/z 283.1 (M+H)⁺.

Step C: methyl 2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) acetate

Under inert nitrogen atmosphere, a mixture of methyl2-(4-(2-methoxy-2-oxoethyl)-2-nitrophenyl-amino) acetate (4.6 g, 16.3mmol), Pd (w/w 10% on carbon, 1.73 g, 1.63 mmol), ammonium formate (15.4g, 245 mmol) in ethanol (100 mL) was stirred at room temperatureovernight. The reaction mixture was filtrated to remove Pd and ammoniumformate. The filtrate obtained was evaporated to dryness. The solid wasdissolved in ethyl acetate (100 mL) and washed with brine. The organicphase was then evaporated to dryness to afford methyl2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) acetate (1.6 g, 45% yield)as yellow solid.

¹H NMR (DMSO-d₆) δ 10.22 (bs, 1H), 6.65-6.58 (m, 3H), 5.92 (bs, 1H),3.69 (s, 2H), 3.64 (s, 3H), 3.46 (s, 2H). LC-MS: m/z 221.1 (M+H)⁺.

Step D: methyl 2-(3-oxo-3,4-dihydroquinoxalin-6-yl) acetate

A mixture of methyl 2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) acetate(3.4 g, 15.5 mmol) and manganese (IV) oxide (13.4 g, 155 mmol) inchloroform (200 mL) was heated to 50° C. overnight. The mixture wasfiltrated to remove manganese (IV) oxide. The filtrate obtained wasevaporated to dryness to afford methyl2-(3-oxo-3,4-dihydroquinoxalin-6-yl) acetate (2.9 g, 86% yield) as greysolid. LC-MS: m/z 219.1 (M+H)⁺.

Step E: methyl 2-(3-methoxyquinoxalin-6-yl) acetate

A mixture of 2-(3-oxo-3,4-dihydroquinoxalin-6-yl) acetate (0.8 g, 3.67mmol) in phosphoryl trichloride (6 mL) was heated to reflux for 2 h. Themixture was evaporated to remove phosphoryl trichloride. The crude oilwas quenched with methanol at room temperature. The mixture was thenevaporated to dryness. The crude was purified with column chromatography(methanol:dichloromethane=1:20) on silica gel to afford methyl2-(3-methoxyquinoxalin-6-yl) acetate (320 mg, 38% yield) as white solid.LC-MS: m/z 233.1 (M+H)⁺.

Step F: methyl 2-(3-methoxyquinoxalin-6-yl)-3-oxobutanoate

Under inert nitrogen atmosphere, to a mixture of methyl2-(3-methoxyquinoxalin-6-yl) acetate (220 mg, 0.948 mmol) intetrahydrofuran (10 mL) at −78° C. was added lithiumhexamethyldisilylamide (2N, 0.95 mL, 1.89 mmol) dropwise. The mixturewas then stirred at the same temperature for 1 h. Acetyl chloride (89mg, 1.14 mmol) was added into the mixture at −78° C. The reactionmixture was warmed slowly to room temperature. The reaction was quenchedwith aqueous ammonium chloride and evaporated to dryness. The residuewas purified with prep-TLC (methanol:dichloromethane=1:20) on silica gelto afford methyl 2-(3-methoxyquinoxalin-6-yl)-3-oxobutanoate (160 mg,62% yield) as white solid. LC-MS: m/z 275.1 (M+H)⁺.

Step G: Compound 254:6-(3-methoxy-quinoxalin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]-pyrimidin-7(4H)-one

A mixture of methyl 2-(3-methoxyquinoxalin-6-yl)-3-oxobutanoate (223 mg,0.814 mmol), 3,4-diphenyl-1H-pyrazol-5-amine (191 mg, 0.814 mmol) andacetate acid (2 mL) in dioxane (8 mL) was heated to 100° C. overnight.The mixture was concentrated to to afford6-(3-methoxy-quinoxalin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]-pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 12.07 (s, 1H), 8.64 (s, 1H), 8.07 (d, J=8 Hz, 1H),7.84 (d, J=2 Hz, 1H), 7.64 (dd, J=8 Hz, 2 Hz, 1H), 7.43-7.50 (m, 5H),7.34-7.38 (m, 5H), 4.08 (s, 3H), 2.27 (s, 3H). LC-MS: m/z 460.2 (M+H)⁺.

Compound 255

Step A: 5-fluoro-2-nitro-(N,N)-di-tert-butyl-carbonoaniline

To a solution of 5-fluoro-2-nitroaniline (5 g, 32 mmol) in CH₂Cl₂ wasadded N,N-dimethylpyridin-4-amine (390 mg, 3.2 mmol) and triethylamine(6.43 g, 64 mmol). The reaction mixture was stirred for 10 mins and thendi-tert-butyl dicarbonate (20 g, 96 mmol) was added slowly and stirredovernight. The reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography on silica gel (eluting PE/EA=10:1)to give the desired product (8 g, 71% yield).

¹H NMR (CHLOROFORM-d) δ: 8.16 (dd, J=9.1, 5.4 Hz, 1H), 7.16-7.24 (m,1H), 7.07 (dd, J=8.3, 2.7 Hz, 1H), 1.41-1.44 (m, 18H).

Step B: methyl2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate

To a solution of2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate (8 g,22.4 mmol) in DMF (20 ml) was added cesium carbonate (7.3 g, 44.8 mmol)and methyl 3-oxobutanoate (2.6 g, 22.4 mmol). The mixture was heated to100° C. for 4 h. The mixture was poured into water and extracted withethyl acetate. The organic phase was washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel (eluting PE/EA=10:1) to give thedesired product (7 g, 69% yield).

Step C: methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate

A solution of methyl2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate (2 g, 4.4mmol) in HCl/MeOH (10 ml) was stirred for 4 h. The reaction mixture wasconcentrated to give the desired product methyl2-(3-amino-4-nitrophenyl)-3-oxobutanoate (1.1 g, 100% yield).

Step D:6-(3-amino-4-nitrophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate (1.1 g,4.3 mmol), 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (1.0 g, 4.3mmol) in AcOH (10 ml) were heated to 120° C. overnight. The reactionmixture was concentrated. The residue was washed with ethyl acetate togive the desired product6-(3-amino-4-nitrophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(710 mg, 38% yield).

¹H NMR (DMSO-d₆) δ: 7.98-8.10 (m, 3H), 7.66 (br. s., 2H), 7.43-7.52 (m,3H), 6.99 (d, J=1.6 Hz, 1H), 6.60 (dd, J=8.9, 1.9 Hz, 1H), 3.07-3.21 (m,4H), 2.33 (s, 3H), 1.71 (br. s., 4H), 1.51-1.63 (m, 2H). LC-MS: m/z445.2 (M+H)⁺.

Step E:6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(3-amino-4-nitrophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(710 mg, 1.6 mmol) in MeOH (20 ml) was added Pd/C (71 mg) under H₂. Thereaction mixture was stirred for 4 h. The mixture was filtered and thefiltrate was concentrated to give the desired product6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(500 mg, 75% yield).

¹H NMR (DMSO-d₆) δ: 11.21 (br. s., 1H), 8.05-8.17 (m, 2H), 7.46 (t,J=7.4 Hz, 2H), 7.35-7.42 (m, 1H), 6.54 (d, J=7.8 Hz, 1H), 6.43 (d, J=1.9Hz, 1H), 6.29 (dd, J=7.8, 1.9 Hz, 1H), 4.49 (br. s., 4H), 3.07 (d, J=5.1Hz, 4H), 2.22-2.29 (m, 3H), 1.66 (br. s., 4H), 1.51-1.61 (m, 2H). LC-MS:m/z 415.2 (M+H)⁺.

Step F: Compound 255:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.24 mmol) in EtOH (10 ml) was added oxalaldehyde (21 mg, 0.36mmol). Then the reaction mixture was heated to 80° C. for 2 h. Thereaction mixture was concentrated to give the desired product5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (CHLOROFORM-d) δ: 8.86-8.93 (m, 2H), 8.21 (d, J=8.6 Hz, 1H), 8.07(s, 1H), 8.02 (br. s., 1H), 7.81-7.88 (m, 1H), 7.54 (br. s., 1H), 7.47(br. s., 3H), 3.06 (br. s., 4H), 2.44 (br. s., 3H), 1.77 (br. s., 2H),1.71 (br. s., 3H), 1.65 (br. s., 2H). LC-MS: m/z 437.4 (M+H)⁺.

Compound 256

Step A: 5-fluoro-N-methyl-2-nitroaniline

To a solution of 2,4-difluoro-1-nitrobenzene (10 g, 63 mmol) in MeCN wasadded CH₃NH₂ (63 ml, 1 mmol/ml in MeOH) at 0° C. The reaction mixturewas stirred for 4 h. The mixture was filtered to give Intermediate 2 (10g) as a yellow solid. LC-MS: m/z 170.2 (M+H)⁺.

Step B: dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate

To a solution of Intermediate 2 (5 g, 29.4 mmol) in DMSO (20 ml) wasadded dimethyl malonate (3.88 g, 29.4 mmol) and cesium carbonate (19.2g, 58.8 mmol). The reaction mixture was heated to 120° C. for 4 h. Thereaction mixture was then poured into water, extracted with ethylacetate, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by column chromatography on silica gel (elutingPE/EA=2:1) to give the desired product (3.4 g).

¹H NMR (DMSO-d₆) δ: 8.13-8.25 (m, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.04 (d,J=1.6 Hz, 1H), 6.67 (dd, J=8.9, 1.6 Hz, 1H), 5.16 (s, 1H), 3.71 (s, 6H)2.92-2.98 (m, 3H). LC-MS: m/z 283.3 (M+H)⁺.

Step C: methyl 2-(3-(methylamino)-4-nitrophenyl)acetate

To a solution of dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate (3.4g, 12 mmol) in DMSO (20 ml) was added saturated NaCl (5 ml). Thereaction mixture was heated to 120° C. for 3 h. The reaction mixture wasthen poured into water, extracted with ethyl acetate, dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel (eluting PE/EA=2:1) to give thedesired product (200 mg).

¹H NMR (DMSO-d₆) δ: 8.19 (d, J=4.3 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H),6.87-6.96 (m, 1H), 6.59 (dd, J=8.9, 1.6 Hz, 1H), 3.76 (s, 3H), 2.95 (d,J=4.8 Hz, 4H). LC-MS: m/z 225.1 (M+H)⁺.

Step D: methyl 2-(3-(methylamino)-4-nitrophenyl)-3-oxobutanoate

To a solution of methyl 2-(3-(methylamino)-4-nitrophenyl)acetate (200mg, 0.89 mmol)) in THF (15 ml) was added slowly LDA (4.5 ml, 2 mmol/mlin THF) at −30° C. Then acetyl chloride (104 mg, 1.34 mmol) was addedslowly. The reaction mixture was stirred for 30 mins at −30° C. andallowed to room temperature for 1 h. The mixture was poured into water,extracted by ethyl acetate, dried over anhydrous Na₂SO₄, filtered, andconcentrated to give the crude product (200 mg) as a yellow liquid,which was used directly to the next step without further purification.

Step E:5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of methyl 2-(3-(methylamino)-4-nitrophenyl)-3-oxobutanoate(crude, 200 mg) and 3,4-diphenyl-1H-pyrazol-5-amine (100 mg, 0.43 mmol)in AcOH (10 ml) was heated to 120° C. overnight. The reaction mixturewas cooled to room temperature. The precipitate was filtered to give thedesired product5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(35 mg). LC-MS: m/z 452.3 (M+H)⁺.

Step F:6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(35 mg, 0.078 mmol) in MeOH (10 ml) was added Pd/C (5 mg) under H₂. Thereaction mixture was stirred for 4 h. The mixture was filtered and thefiltrate was concentrated to give the desired product6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(10 mg) as a solid. LC-MS: m/z 422.2 (M+H)⁺.

Step G: Compound 256:5-methyl-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(10 mg, 0.024 mmol) in HCOOH (5 ml) was heated to 120° C. for 1 h. Thereaction mixture was concentrated in vacuo to give the desired product5-methyl-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (METHANOL-d₄) δ: 8.21 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.60 (s,1H), 7.27-7.57 (m, 11H), 3.95 (s, 3H), 2.28 (s, 3H). LC-MS: m/z 432.0(M+H)⁺.

Compound 257 and Compound 258

Step A: methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate

A mixture of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (5 g, 0.024 mol),K₂CO₃ (6.5 g, 0.048 mol), and 1-(chloromethyl)-4-methoxybenzene (5.6 g0.036 mol) was heated to 60° C. for 4 h. The reaction mixture was pouredinto water, extracted with ethyl acetate, dried over anhydrous Na₂SO₄,filtered, concentrated. The residue was purified by columnchromatography on silica gel (eluting PE/EA=3:1) to give the desiredproduct (2 g, 53% yield). LC-MS: m/z 332.2 (M+H)⁺.

Step B: methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3-oxobutanoate

To a solution of methyl2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate (2 g, 6.0 mmol) in THF(50 ml) was added slowly LDA (3 ml, 2 mmol/ml in THF) at −30° C. Thenacetyl chloride (702 mg, 9.0 mmol) was added slowly. The reactionmixture was stirred for 30 mins at −30° C. and allowed to roomtemperature for 1 h. The mixture was poured into water, extracted withethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentratedto give the crude product (1.5 g) as a yellow liquid, which was useddirectly to next step without further purification.

Step C:6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3-oxobutanoate (crude, 1.5 g)and 3,4-diphenyl-1H-pyrazol-5-amine (1 g, 4.25 mmol) in AcOH (10 ml) washeated to 120° C. overnight. The reaction mixture was cooled to roomtemperature. The precipitate was filtered to give the desired product6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(600 mg, 32% yield). LC-MS: m/z 439.3 (M+H)⁺.

Step D:6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(600 mg, 1.37 mmol) in MeOH (50 ml) was added Pd/C (60 mg) under H₂. Thereaction mixture was stirred for 4 h. The mixture was filtered and thefiltrate was concentrated to give the desired product6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(450 mg, 80% yield).

¹H NMR (DMSO-d₆) δ: 11.96 (s, 1H), 10.84 (br. s., 1H), 9.88 (br. s.,2H), 7.37-7.51 (m, 5H), 7.24-7.37 (m, 6H), 7.19 (dd, J=8.3, 1.9 Hz, 1H),7.11 (d, J=8.3 Hz, 1H), 2.20 (s, 3H). LC-MS: m/z 409.2 (M+H)⁺.

Step E:2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide

A mixture of6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(450 mg, 1.1 mmol), 2-chloroacetyl chloride (136 mg, 1.2 mmol), andK₂CO₃ (455 mg, 3.3 mmol) in acetone (50 ml) was heated to 80° C.overnight. The reaction mixture was poured into water, extracted withethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentrated.The resultant solid was washed with ethyl acetate to give the desiredproduct2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide(250 mg, 47% yield). LC-MS: m/z 485.2 (M+H)⁺.

Step F: Compound 257:6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide(250 mg, 0.52 mmol), and Cs₂CO₃ (258 mg, 1.04 mmol) in acetone (40 ml)was heated to 100° C. overnight. The reaction mixture was poured intowater, extracted with ethyl acetate, dried over anhydrous Na₂SO₄,filtered, and concentrated to give the desired product6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.93 (s, 1H), 10.79 (s, 1H), 7.38-7.56 (m, 5H),7.24-7.38 (m, 4H), 7.01 (d, J=8.9 Hz, 1H), 6.81-6.92 (m, 2H), 4.63 (s,2H), 2.18 (s, 3H). LC-MS: m/z 449.0 (M+H)⁺.

Step G: Compound 258:6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(110 mg, 0.25 mmol) in THF (20 ml) was added BH₃.THF (1 ml, 1 mmol/ml).The reaction mixture was heated to 80° C. for 4 h. The reaction mixturewas then cooled to room temperature. MeOH (10 ml) was added carefully,and then the reaction mixture was stirred for 10 mins. The mixture wasconcentrated to give the desired product.

¹H NMR (DMSO-d₆) δ: 11.82 (br. s., 1H), 7.39-7.51 (m, 5H), 7.33 (br. s.,5H), 6.68 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J=8.2 Hz, 1H), 5.80(br. s., 1H), 4.16 (br. s., 2H), 3.31 (br. s., 2H), 2.17 (s, 3H). LC-MS:m/z 435.0 (M+H)⁺.

Compound 259

Step A: methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)acetate

To a solution of methyl 2-(4-hydroxy-3-methoxyphenyl)acetate (1 g, 5.1mmol) in CH₃CN (50 ml) was added K₂CO₃ (1.4 g, 10.2 mmol) and PMBCl (795mg, 5.1 mmol). Then the mixture was heated to 80° C. for 2 h. Thereaction mixture was poured into water, extracted with ethyl acetate,dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified by column chromatography on silica gel (eluting PE/EA=2:1) togive the desired product (900 mg, 56% yield). LC-MS: m/z 317.3 (M+H)⁺.

Step B: methyl2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate

To a solution of methyl2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)acetate (900 mg, 2.85 mmol)in THF (15 ml) was added slowly LDA (4.5 ml, 2 mmol/ml in THF) at −30°C. Then acetyl chloride (266 mg, 1.34 mmol) was added slowly. Thereaction mixture was stirred for 30 mins at −30° C. and allowed to roomtemperature for 1 h. The mixture was poured into water, extracted withethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentratedto give the crude product (700 mg) as a yellow liquid, which was useddirectly to the next step without further purification.

Step C:6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate (crude, 400mg) and 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH (10ml) was heated to 120° C. overnight. The reaction mixture was cooled toroom temperature. The precipitate was filtered to give the desiredproduct6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg, 26% yield). LC-MS: m/z 544.2 (M+H)⁺.

Step D: Compound 259:6-(4-hydroxy-3-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg, 0.22 mmol) in MeOH (10 ml) was added 4N HCl/dioxane solution(10 ml). The reaction mixture was stirred for 1 h. When the startingmaterial was consumed, the mixture was concentrated in vacuo to give thedesired product6-(4-hydroxy-3-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.85 (s, 1H), 9.04 (s, 1H), 7.37-7.52 (m, 6H),7.27-7.37 (m, 6H), 6.79-6.90 (m, 2H), 6.72 (dd, J=8.1, 1.9 Hz, 1H), 2.19(s, 3H). LC-MS: m/z 424.1 (M+H)⁺.

Compound 260 & Compound 261

Step A: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate

A mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl) acetate (4.3 g, 20.5mmol), ((2-bromoethoxy)methyl)benzene (7.88 g, 36.8 mmol), potassiumcarbonate (5.66 g, 41 mmol) in N,N-dimethylformamide (50 mL) was heatedto 80° C. for 18 h. The mixture was cooled to room temperature, pouredinto water (100 mL), and extracted with ethyl acetate (100 mL) threetimes. The combined organic phase was washed with brine, dried oversodium sulfate and evaporated to dryness. The crude was purified bycolumn chromatography (ethyl acetate:petroleum ether=1:5) to affordethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate (3.8 g, 54%yield) as a colorless oil.

Step B: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate

To a mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate(690 mg, 2 mmol) in tetrahydrofuran (10 mL) was added lithiumdiisopropylamide (2N, 1 mL, 2 mmol) at −78° C. under nitrogenatmosphere. The mixture was stirred at the same temperature for 1 h.Acetyl chloride (156 mg, 2 mmol) was added into the mixture at −78° C.slowly. After addition, the mixture was stirred at −78° C. for 1 h andwarmed slowly to room temperature overnight. The mixture was quenched byadding aqueous ammonium chloride to pH 6-7 and extracted with ethylacetate (20 mL) three times. The combined organic phase was washed withbrine, dried over sodium sulfate and evaporated to dryness. The crudewas purified by column chromatography on silica gel (ethylacetate:petroleum ether=1:5) to afford ethyl2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 38%yield) as a colorless oil. LC-MS: m/z 387.2 (M+H)⁺.

Step C:6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]yrimidin-7(4H)-one

A mixture of ethyl2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg,0.725 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (170 mg, 0.725 mmol) inacetic acid (5 mL) was heated to reflux for 2 h. The mixture wasevaporated to remove acetic acid. The residue was purified with columnchromatography (methanol:dichloromethane=1:20) to afford6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg, 30% yield) as a yellow solid. LC-MS: m/z 558.2 (M+H)⁺.

Step D: Compound 260 & Compound 261:6-(3,4-dihydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenyl-pyrazolo[1,5-a]yrimidin-7(4H)-one(200 mg, 0.359 mmol) and tribromoborane (1M in DCM, 2 mL) was stirred atroom temperature for 1 h. The reaction was quenched with methanol at 0°C. The mixture was evaporated to dryness to afford6-(3,4-dihydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneand6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

6-(3,4-dihydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 260)

¹H NMR (DMSO-d₆) δ: 11.82 (s, 1H), 7.37-7.52 (m, 5H), 7.20-7.37 (m, 5H),6.78 (d, J=8.06 Hz, 1H), 6.66-6.73 (m, 1H), 6.55 (d, J=7.79 Hz, 1H),2.17 (s, 3H). LC-MS: m/z 410.1 (M+H)⁺.

6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 261)

¹H NMR (DMSO-d₆) δ: 11.85 (s, 1H), 8.82 (s, 1H), 7.38-7.58 (m, 5H),7.24-7.38 (m, 5H), 6.81-6.92 (m, 2H), 6.73 (dd, J=8.06, 1.88 Hz, 1H),4.91 (t, J=6.04 Hz, 1H), 3.97 (t, J=4.97 Hz, 2H), 3.74 (q, J=5.46 Hz,2H), 2.06-2.22 (m, 3H). LC-MS: m/z 454.2 (M+H)⁺.

Compound 262

Step A:5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (8.43 g,34.8 mmol) and methyl 3-oxobutanoate (9 g, 69.2 mmol) in acetic acid (5mL) was heated to reflux for 2 h. The mixture was cooled to roomtemperature. The suspension obtained was filtered. The resulting solidwas washed with water and cold methanol to afford5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(7.9 g, 74% yield) as a white solid. LC-MS: m/z 309.2 (M+H)⁺.

Step B:5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(5.5 g, 17.9 mmol) in N,N-dimethylformamide (50 mL) was added sodiumhydride (1.4 g, 35.8 mmol) slowly at 0° C. After addition, the mixturewas stirred at 0° C. for 1 h. (2-(Chloromethoxy)ethyl)trimethylsilane(3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at roomtemperature overnight. The mixture was quenched with brine and extractedwith ethyl acetate (50 mL) three times. The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo to dryness. The residue was purified by column chromatography(methanol:dichloromethane=1:20) to afford5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(2.5 g, 35% yield) as a white solid. LC-MS: m/z 439.2 (M+H)⁺.

Step C:6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)-methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(1.2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) indichloromethane (20 mL) at room temperature was added N-bromosuccinimide(0.58 g, 3.47 mmol) at room temperature. Then the mixture was stirred atroom temperature for 2 h. The mixture was concentrated. The residue waspurified by column chromatography (methanol:dichloromethane=1:20) toafford6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(1.3 g, 80% yield) as a white solid. LC-MS: m/z 519.2, 517.2 (M+H)⁺.

Step D:6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)-ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.194 mmol) and 4-hydroxyphenylboronic acid (41 mg, 0.293 mmol)in dioxane/H₂O (5 mL/1 mL) was added1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogenatmosphere overnight. The reaction mixture was filtered and concentratedin vacuo. The residue was purified by column chromatography(methanol:dichloromethane=1/20) to afford6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(60 mg, 59% yield) as a white solid. LC-MS: m/z 531.3 (M+H)⁺.

Step E: Compound 262:6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 0.113 mmol) inCF₃COOH (2 mL) was heated to 60° C. for 3 h. The mixture was cooled toroom temperature and concentrated in vacuo to remove solvent. Theresulting residue was washed with saturated aqueous sodium bicarbonate.The suspension obtained was filtered to afford6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (Methanol-d₄) δ: 8.07 (d, J=6.72 Hz, 2H), 7.45 (d, J=7.52 Hz,3H), 7.16 (d, J=8.33 Hz, 2H), 6.88 (d, J=8.33 Hz, 2H), 3.06-3.16 (m,4H), 2.34 (s, 3H), 1.75-1.73 (m, 4H), 1.63-1.62 (m, 2H). LC-MS: m/z401.2 (M+H)⁺.

Compound 263

Step A:2,2,2-trifluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)acetamide

To a solution of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-amine (3 g, 14mmol) in THF (50 ml) was added slowly NaHMDS (14 ml, 1 mmol/ml) at −78°C. After addition, the mixture was stirred at −78° C. for 30 mins, andthen allowed to −30° C. for 30 mins. TFAA (2 g, 21 mmol) was addedslowly, and the mixture was stirred at −30° C. for 20 mins. The reactionmixture was allowed to warm to room temperature overnight. The mixturewas poured into water, extracted with ethyl acetate, dried overanhydrous Na₂SO₄, and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (eluting PE/EA=1:1) to give thedesired product2,2,2-trifluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)acetamide(2 g, 46% yield).

¹H NMR (DMSO-d₆) δ: 12.14 (s, 1H), 8.76 (s, 1H), 5.52 (s, 2H), 3.63-3.71(m, 2H), 3.51-3.61 (m, 2H), 0.80-0.98 (m, 9H). LC-MS: m/z 311.2 (M+H)⁺.

Step B: Compound 263:2,2,2-trifluoro-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)acetamide

To a solution of2,2,2-trifluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)acetamide(200 mg, 0.65 mmol) in NMP (10 ml) was added t-BuOk (1 ml, 1 mmol/ml inTHF). The reaction mixture was stirred for 30 mins, and then5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.22 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h. The mixture was poured into water, extracted withethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentratedto to give the desired product2,2,2-trifluoro-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)acetamide.

¹H NMR (DMSO-d₆) δ: 12.23 (s, 1H), 9.65 (br. s., 1H), 8.95 (br. s., 1H),8.35 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 7.71 (d,J=8.6 Hz, 1H), 7.58 (dd, J=7.9, 4.2 Hz, 2H), 7.46 (br. s., 4H),7.19-7.42 (m, 6H), 4.32 (br. s., 2H). LC-MS: m/z 540.0 (M+H)⁺.

Compound 264

Step A:N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)hydrazinecarboximidamide

A mixture of5-(aminomethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 222, 200 mg, 0.47 mmol) and methyl hydrazinecarbimidothioate(100 mg, 0.94 mmol) in EtOH (20 ml) in a seal tube were heated to 120°C. overnight. The reaction mixture was concentrated to dryness. Theresultant solid was washed with ethyl acetate to give the desiredproduct (170 mg, 75% yield);

¹H NMR (DMSO-d₆) δ: 8.62 (br. s., 1H), 7.49-7.58 (m, 4H), 7.31-7.42 (m,4H), 7.17-7.30 (m, 4H), 7.04-7.14 (m, 1H), 6.96 (d, J=8.6 Hz, 2H), 4.72(br. s., 2H), 4.07 (br. s., 2H), 3.80 (s, 3H). LC-MS: m/z 480.2 (M+H)⁺.

Step B: Compound 264:5-(((1H-1,2,4-triazol-3-yl)amino)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution ofN-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)hydrazinecarboximidamide(170 mg, 0.355 mmol) in HCOOH (5 ml) and trimethoxymethane (5 ml) washeated to 150° C. for 4 h. When the reaction mixture was consumed, themixture was concentrated to dryness. The residue was suspended in DMSO(10 ml) and stirred for 30 mins at 5° C. to give the desired product5-(((1H-1,2,4-triazol-3-yl)amino)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 8.44 (s, 1H), 7.28-7.49 (m, 11H), 7.11-7.24 (m,J=8.6 Hz, 2H), 6.87-7.04 (m, J=8.6 Hz, 2H), 4.90 (s, 2H), 3.74-3.86 (m,3H). LC-MS: m/z 490.0 (M+H)⁺.

Compound 265

Step A: 4-(4,4-difluorocyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine

To a solution of 3-phenyl-1H-pyrazol-5-amine (1 g, 6.3 mmol) and4,4-difluorocyclohexanone (844 mg, 6.3 mmol) in AcOH (10 ml) were heatedto 80° C. for 3 h. The reaction mixture was concentrated to give thecrude product, which was used directly to the next step without furtherpurification.

Step B: Compound 265:3-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol)and 4-(4,4-difluorocyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (100mg, crude) in AcOH (10 ml) was heated to 120° C. for 2 h. The reactionmixture was cooled to room temperature to give the desired product.

¹H NMR (DMSO-d₆) δ: 11.86 (s, 1H), 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.40(d, J=7.3 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H),7.67-7.81 (m, 3H), 7.58 (dd, J=8.3, 4.3 Hz, 1H), 7.38-7.52 (m, 3H), 5.78(br. s., 1H), 2.78 (t, J=15.0 Hz, 2H), 2.37 (br. s., 2H), 2.31 (s, 3H),2.11-2.23 (m, 2H). LC-MS: m/z 469.8 (M+H)⁺.

Compound 266

Step A: tert-butyl4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate

A suspension of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 200 mg, 0.39 mmol) andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(341 mg, 1.16 mmol), PdCl₂(dppf) (28 mg, 0.04 mmol) and Na₂CO₃ (82 mg,0.78 mmol) in 1.4-dioxane/water (10 mL/1 mL) was stirred and heated to85° C. for 16 h under N₂ atmosphere. The reaction was then cooled to RTand filtered. The dark filtrate was concentrated in vacuo. The residuewas purified by flash column chromatography, eluting with PE/EA (4/1),to desired product (40 mg, 18% yield) as a white solid. LC-MS: m/z 605.3(M+H)⁺.

Step B:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of tert-butyl4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate(40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 mL, 5 mmol) was stirredat RT for 1 h. The mixture was then concentrated to dryness. The residuewas dissolved into conc. hydrochloric acid (10 mL), and stirred at 100°C. for 24 h to get the desired product.

¹H NMR (DMSO-d₆) δ: 12.90 (br. s., 1H), 11.34 (br. s., 1H), 8.13 (d,J=7.2 Hz, 2H), 7.99-7.51 (m, 2H), 7.49-7.37 (m, 3H), 3.08 (br. s., 4H),2.45 (s, 3H), 1.66 (br. s., 4H), 1.59 (br. s., 2H). LC-MS: m/z 375.2(M+H)⁺.

Compound 267

Step F: Compound 267:6-(1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 255, 100 mg, 0.24 mmol) in HCOOH (10ml) was stirred at 100° C. for 2 h. The reaction mixture wasconcentrated and washed with aq. NaHCO₃ solution to give the desiredproduct6-(1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 12.47 (br. s., 1H), 11.47 (br. s., 1H), 8.25 (s,1H), 8.08-8.17 (m, 2H), 7.57 (br. s., 2H), 7.44-7.50 (m, 2H), 7.34-7.42(m, 1H), 7.12 (br. s., 1H), 3.11 (br. s., 4H), 2.26 (s, 3H), 1.67 (br.s., 4H), 1.59 (br. s., 2H). LC-MS: m/z 425.3 (M+H)⁺.

Compound 268

Step A:6-(2-amino-1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To the solution of6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.24 mmol) in CH₃CN (10 mL) and H₂O (5 mL) was added cyanicbromide (28 mg, 0.256 mmol). The mixture was stirred at r.t. for 1 h.The mixture was concentrated to give the crude product, which was washedwith aq. NaHCO₃ solution and filtered to give the desired product6-(2-amino-1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 10.64 (br. s., 1H), 8.31-8.33 (d, 2H), 7.35-8.39 (m,2H), 7.24-7.28 (m, 1H), 6.98-7.04 (m, 2H), 6.74 (m, 1H), 5.99 (br. s.,1H), 3.23 (br. s., 4H), 2.08 (s, 3H), 1.66 (br. s., 4H), 1.54 (br. s.,2H). LC-MS: m/z 440.3 (M+H)⁺.

Compound 269

Step A: ethyl 2-(4-methoxyphenyl)-3-oxobutanoate

To a solution of ethyl 2-(4-methoxyphenyl)acetate (5 g, 25.7 mmol) inTHF (100 mL) was added LDA (1.5 M in THF, 20 mL, 30.84 mmol) dropwise at−30˜−35° C. The mixture was stirred at −30˜−35° C. for 30 min, andacetyl chloride (2.1 g, 27 mmol) was added dropwise. Then the mixturewas stirred at rt for 6 h. The mixture was poured into saturated NH₄Cland extracted with EA (3*100 mL). The combined organic phase was washedwith brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography to afford thedesired ethyl 2-(4-methoxyphenyl)-3-oxobutanoate as a brown oil (5.2 g,86% yield).

Step B:6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of ethyl 2-(4-methoxyphenyl)-3-oxobutanoate (292 mg, 1.24mmol) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (300 mg, 1.24mmol) in AcOH (10 mL) was stirred at 95° C. for 4 h. After cooling toroom temperature, the solids were collected by filtration, wash withethyl acetate, and dried under vacuum to give6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(210 mg, 41% yield) as a white solid. LC-MS: m/z 415.1 (M+H)⁺.

Step C: Compound 269:6-(4-methoxyphenyl)-4,5-dimethyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(210 mg, 0.49 mmol) and Cs₂CO₃ (320 mg, 0.98 mmol) in DMF (10 mL) wasadded MeI (103 mg, 0.735 mmol). The mixture was then stirred at rtovernight to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.62 (br. s., 2H), 7.45 (d, J=2.15 Hz,3H), 7.23 (m, J=8.33 Hz, 2H), 6.98 (m, J=8.33 Hz, 2H), 4.26 (s, 3H),3.86 (s, 3H), 3.00 (d, J=11.55 Hz, 4H), 2.31 (s, 3H), 1.78 (br. s., 4H),1.66 (br. s., 2H). LC-MS: m/z 429.0 (M+H)⁺.

Compound 271

Step A: methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)acetate

To a solution of methyl 2-(4-hydroxyphenyl)acetate (5.0 g, 30 mmol) inDMF (25 ml) was added K₂CO₃ (8.3 g, 60 mmol) at r.t. under N₂atmosphere. After the mixture was stirred at r.t. for 30 min,1-(bromomethyl)-4-methoxybenzene (7.2 g, 36 mmol) was added dropwise,and the mixture was stirred at r.t. for 2 h. The mixture was poured intoH₂O (100 mL) and extracted with EA (3*50 mL). The combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was recrystallized from EtOH to afford the titlecompound 2 as a white solid (5.6 g, 65% yield). LC-MS: m/z 287.1 (M+H)⁺.

Step B: methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate

To a solution of Intermediate 2 (4.6 g, 16 mmol) in THF (50 mL) wasadded LDA (2 mol/l in THF, 16 ml) dropwise at −60° C. The mixture wasstirred at −60° C. for 30 min. Then acetyl chloride (1.5 g, 19.2 mmol)was added dropwise. The mixture was stirred at −60° C. for 30 min andstirred at r.t. for 1 h. The mixture was diluted with EA (50 mL) andquenched with saturated NH₄Cl. The organic phase was separated andwashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound 3 as a yellow oilwhich was used to the next step without purification (5.2 g, 99% yield).

Step C:6-(4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of Intermediate 3 (5.3 g, 16 mmol) and3-phenyl-1H-pyrazol-5-amine (1.9 g, 12 mmol) in AcOH (10 ml) wasrefluxed for 1 h. The reaction mixture was cooled to room temperature.The precipitate was filtered off and washed with EA (3*5 mL) to affordthe title compound 4 (3.0 g, 43% yield). LC-MS: m/z 438.1 (M+H)⁺.

Step D:6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 4 (3.0 g, 6.9 mmol) in DMF (50 mL) wereadded Cs₂CO₃ (6.8 g, 20.7 mmol) and iodomethane (2.9 g, 20.7 mmol). Themixture was then stirred at r.t. overnight. The mixture was poured intowater (200 mL). The white precipitate was filtered off, washed with H₂O(3*5 mL) and EA (3*5 mL) to afford the title compound 5 as a white solid(2.8 g, 88% yield). LC-MS: m/z 452.1 (M+H)⁺.

Step E:3-bromo-6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of Intermediate 5 (2.8 g, 6.1 mmol) in DCM (50 ml) wasadded N-Bromosuccinimide (1.2 g, 6.7 mmol). The reaction mixture wasthen stirred at r.t. overnight. The mixture was poured into water (200mL). The organic phase was separated, washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford the title compound6 (3.1 g, 94% yield) as a white solid. LC-MS: m/z 530.1/532.1 (M+H)⁺.

Step F:6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenyl-3-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 6 (200 mg, 0.38 mmol), thiophen-2-ylboronicacid (242 mg, 1.89 mmol), Pd(dppf)Cl₂ (100 mg, 0.12 mmol) and Cs₂CO₃(246 mg, 0.76 mmol) in 1.4-dioxane (16 mL) and H₂O (2 ml) was stirred at90° C. overnight under N₂ atmosphere. The reaction mixture was thencooled to r.t., diluted with DCM (50 mL) and filtered through celite.The filtrate was washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by prep-TLCto afford compound 7 (70 mg, 35% yield). LC-MS: m/z 534.1 (M+H)⁺.

Step G:6-(4-hydroxyphenyl)-4,5-dimethyl-2-phenyl-3-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 7 (25 mg, 0.05 mmol) in DCM (5 mL) wasadded TFA (0.5 mL). The reaction mixture was stirred at r.t. for 2 h.The mixture was concentrated in vacuo. The residue was dissolved in DCM(5 mL), washed with saturated NaHCO₃ solution and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to give the title compound 8.

¹H NMR (CHLOROFORM-d) δ: 7.54-7.63 (m, 2H), 7.43-7.48 (m, 1H), 7.21-7.33(m, 3H), 7.08-7.15 (m, 2H), 6.90-7.05 (m, 2H), 6.72-6.81 (m, 2H), 3.54(br. s., 3H), 2.24 (br. s., 3H). LC-MS: m/z 414.1 (M+H)⁺.

Compound 272

Step A: 2-(3,3-difluoropyrrolidin-1-yl)acetonitrile

The mixture of 3,3-difluoropyrrolidine hydrochloride (3.6 g, 24.8 mmol),2-bromoacetonitrile (3.0 g, 24.8 mmol), and K₂CO₃ (10.3 g, 74.4 mmol) inCH₃CN (50 mL) was stirred at 80° C. overnight. Then the mixture wascooled to r.t. and filtered. The filtrate was poured into water (100 mL)and extracted with EA (30 mL*3). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford the title compound 2 (2.9 g, 80% yield) which was directly usedto the next step without further purification. LC-MS: m/z 147.0 (M+H)⁺.

Step B: 2-(3,3-difluoropyrrolidin-1-yl)-3-oxo-3-phenylpropanenitrile

To a mixture of Intermediate 2 (2.9 g, 20 mmol) and methyl benzoate (2.7g, 20 mmol) in THF (40 mL) was added NaHMDS (2 mol/L in THF, 20 mL) at0° C. The mixture was stirred at r.t. overnight. The reaction mixturewas diluted with EA (50 mL) and quenched with saturated NH₄Cl. Theorganic phase was separated, washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford the title compound 3 as awhite solid (4.9 g, 97% yield) which was used to the next step withoutpurification. LC-MS: m/z 251.0 (M+H)⁺.

Step C: 4-(3,3-difluoropyrrolidin-1-yl)-3-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 3 (4.9 g, 19.6 mmol) and hydrazine hydrate(1.5 g, 29.4 mmol) in EtOH/AcOH (4/1.40 mL/10 mL) was refluxedovernight. Then the mixture was cooled to r.t. and evaporated. Theresidue was dissolved in EA (50 mL) and neutralized with 10% NaHCO₃. Theorganic phase was separated, and the the water phase was extracted withEA (25 mL*3). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo to afford the titlecompound 4 as a yellow solid (5.1 g, 98%) which was used to the nextstep without purification. LC-MS: m/z 265.1 (M+H)⁺.

Step D:3-(3,3-difluoropyrrolidin-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 4 (500 mg, 1.1 mmol) and methyl2-(4-methoxyphenyl)-3-oxobutanoate (359 mg, 1.6 mmol) in AcOH (10 mL)was stirred at 100° C. for 1 h. Then the mixture was cooled to r.t. toafford the title compound 5.

¹H NMR (DMSO-d₆) δ: 11.80 (br. s., 1H), 7.96-8.00 (m, 2H), 7.38-7.50 (m,3H), 7.23 (d, J=8.6 Hz, 9H), 6.99 (d, J=8.6 Hz, 2H), 3.80 (s, 3H), 3.59(t, J=12.8 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 2.43-2.56 (m, 2H), 2.25 (s,3H). LC-MS: m/z 437.7 (M+H)⁺.

Compound 273

Step A: 1-ethyl 3-methyl 2-(4-methoxyphenyl)malonate

To a solution of methyl 2-(4-methoxyphenyl)acetate (5.0 g, 27.7 mmol) inTHF (50 ml) was added LDA (2 mol/L in THF, 16.6 ml) dropwise at −60° C.The mixture was stirred at −60° C. for 30 min. Then ethylcarbonochloridate (3.6 g, 33.2 mmol) was added dropwise. The mixture wasstirred at −60° C. for 30 min and then stirred at r.t. for 2 h. Themixture was diluted with EA (50 mL) and quenched with saturated NH₄Cl.The organic phase was separated and washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (PE/EA=20:1) to afford the titlecompound 2 as a colorless oil (3.0 g, 43% yield). LC-MS: m/z 253.1(M+H)⁺.

Step B:5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 2 (1.0 g, 4.0 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (933 mg, 4.0 mmol) in tributylamine (10mL) was stirred at 185° C. for 1 h and then cooled to room temperature.The precipitate was collected by filtration, washed with MeOH (3*10 mL)to afford the title compound 3 as a white solid (1.1 g, 67% yield).

¹H NMR (DMSO-d₆) δ: 11.57 (br. s, 1H), 7.26-7.49 (m, 12H), 6.90-6.99 (m,2H), 3.78 (s, 3H). LC-MS: m/z 410.1 (M+H)⁺.

Step C:5-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 3 (80 mg, 0.2 mmol) in DCM (3 mL) wasadded borontribromide (0.2 mL) at 0° C. dropwise. The mixture wasstirred at 0° C. for 2 h. The reaction was quenched with MeOH at 0° C.and concentrated in vacuo to afford the desired compound 4.

¹H NMR (DMSO-d₆) δ: 9.66 (br. s., 1H), 8.93 (br. s., 1H), 7.39-7.50 (m,4H), 7.17-7.36 (m, 8H), 6.62 (d, J=8.6 Hz, 2H). LC-MS: m/z 396.1 (M+H)⁺.

Compound 274

Step A: N-(3,4-diphenyl-1H-pyrazol-5-yl)formamide

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (5.0 g, 21.3 mmol) informic acid (30 mL) was refluxed for 1 h. The mixture was evaporated,and the residue was dissolved in EA (50 mL), washed with 10% NaHCO₃aqueous solution, water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(PE/EA 1:1) to afford the title compound 2 as a light yellow solid (4.0g, 72% yield). LC-MS: m/z 264.1 (M+H)⁺.

Step B: N-methyl-3,4-diphenyl-1H-pyrazol-5-amine

To a solution of Intermediate 2 (4.0 g, 15.2 mmol) in THF (30 mL) wasadded borane-THF (1 mol/L in THF, 15.2 mL) dropwise at 0° C. The mixturewas stirred at r.t. overnight. The reaction was quenched by carefuladding MeOH and concentrated in vacuo. The residue was purified by flashchromatography to afford the title compound 3 as a white solid (2.1 g,56%). LC-MS: m/z 250.1 (M+H)⁺

Step C:5-hydroxy-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 3 (200 mg, 0.8 mmol) and 1-ethyl 3-methyl2-(4-methoxyphenyl)malonate (200 mg, 0.8 mmol) in AcOH (5 mL) wasstirred at 160° C. through microwave irradiation for 1 h and cooled toroom temperature to afford the title compound 4.

¹H NMR (DMSO-d₆) δ: 7.33-7.49 (m, 9H), 7.22-7.33 (m, 3H), 6.94 (d, J=8.6Hz, 2H), 3.78 (s, 3H), 3.05 (s, 3H). LC-MS: m/z 424.7 (M+H)⁺.

Compound 275

Step A: dimethyl 2-(quinolin-6-yl)malonate

To a solution of methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) inTHF (30 ml) was added LDA (2 mol/L in THF, 7.4 ml) dropwise at −60° C.The mixture was stirred at −60° C. for 30 min. Then methylcarbonochloridate (1.0 g, 10.9 mmol) was added dropwise. The mixture wasstirred at −60° C. for 30 min and stirred at r.t. for 2 h. The mixturewas diluted with EA (30 mL) and quenched with saturated NH₄Cl. Theorganic phase was separated and washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (PE/EA=20:1) to afford the title compound 2 as acolorless oil (1.0 g, 39% yield). LC-MS: m/z 260.0 (M+H)⁺.

Step B:5-hydroxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 2 (260 mg, 1.0 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (212 mg, 0.9 mmol) in tributylamine (10mL) was stirred at 185° C. for 1 h and cooled to room temperature. Theprecipitate was collected by filtration to afford the title compound 3.

¹H NMR (DMSO-d₆) δ: 9.95 (br. s., 1H), 8.75 (d, J=3.8 Hz, 1H), 8.30-8.39(m, 2H), 8.26 (d, J=7.8 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.39-7.48 (m,3H), 7.19-7.37 (m, 8H). LC-MS: m/z 431.1 (M+H)⁺.

Compound 276

Step A:N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(Synthesized in Scheme of Compound 101, 400 mg, 0.91 mmol), acetamide(230 mg, 1.81 mmol), Pd(OAc)₂ (40.5 mg, 0.18 mmol), Xantphos (158 mg,0.27 mmol) and Cs₂CO₃ (650 mg, 1.99 mmol) in 1.4-dioxane (30 ml) wasreacted in microwave reactor at 100° C. for 45 min under N₂ atmosphere.The reaction was then cooled to RT and filtered. The dark filtrate wasconcentrated in vacuo and purified by flash column chromatography,eluting with DCM/MeOH (40/1), to get the desired product as a yellowsolid (100 mg, 23% yield). LC-MS: m/z 464.2 (M+H)⁺.

Step B:N-(7-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide

To a solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide(70 mg, 0.15 mmol) in DCM (2 mL) was carefully added BBr₃ (1.0 M in DCM,0.5 ml, 5 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. Thereaction was quenched by careful adding ice water at 0° C. Theprecipitated solids were filtered and purified by prep-HPLC to get thedesired product as a yellow solid (50 mg, 75% yield). LC-MS: m/z 437.2(M+H)⁺.

Step C:5-amino-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

TheN-(7-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide(50 mg, 0.11 mmol) and NaOH (17.8 mg, 0.44 mmoL) in EtOH (10 mL) andwater (0.5 mL) was stirred at 40° C. for 14 h. Then the mixture wasconcentrated to get the desired product.

¹H NMR (DMSO-d₆) δ: 9.20 (br. s., 1H), 7.53 (d, J=6.0 Hz, 2H), 7.42 (d,J=6.8 Hz, 2H), 7.35-7.30 (m, 3H), 7.20 (t, J=7.6 Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.71 (br. s., 2H). LC-MS: m/z 395.6(M+H)⁺.

Compound 277

Step A: 2-cyclohexylacetonitrile

A mixture of 2-cyclohexenylacetonitrile (2.0 g, 16.5 mmol) and Pd(OH)₂/C(200 mg, 10%) in MeOH (100 mL) was stirred at RT under H₂ atmosphere for10 h. The mixture was filtered and concentrated to get the desiredproduct as a yellow solid (1.8 g, 90% yield). LC-MS: m/z 124.2 (M+H)⁺.

Step B: 2-cyclohexyl-3-oxo-3-phenylpropanenitrile

To a solution of 2-cyclohexylacetonitrile (1.8 g, 14.6 mmol) in THF (100mL) was added LDA (2.0 M in THF, 8.8 mL, 17.5 mmol) dropwise at −78° C.The mixture was stirred at −78° C. for 30 min, and benzoyl chloride(0.17 mL, 2.33 mmolo) was added dropwise. Then the mixture was slowlywarmed to RT and stirred for 10 h. The mixture was poured slowly tosaturated aq.NH₄Cl and extracted with EA (30 mL*3). The combined organicphase was washed with brine, dried over anhydrous MgSO₄ and concentratedin vacuo to get the desired product as a yellow oil (2.9 g, 88% yield).LC-MS: m/z 228.2 (M+H)⁺.

Step C: 4-cyclohexyl-3-phenyl-1H-pyrazol-5-amine

The solution of 2-cyclohexyl-3-oxo-3-phenylpropanenitrile (2.9 g, 12.8mmol) and hydrazine hydrate (1.9 g, 38.6 mmol) in EtOH/AcOH (30 mL/6 mL)was heated to reflux for 16 h under N₂ protection. The reaction mixturewas concentrated, filtered, washed with Et₂O, and dried to get thedesired product as a yellow oil (2.9 g, 96% yield). LC-MS: m/z 242.1(M+H)⁺.

Step D:3-cyclohexyl-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 4-cyclohexyl-3-phenyl-1H-pyrazol-5-amine (230 mg, 0.96mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (300 mg, 1.24 mmol) inAcOH (5 mL) was stirred at 100° C. for 1 h. After removal of AcOH, 10%of NaHCO₃ was added. The precipitate was filtered, washed with MeOH, anddried to get the desired product.

1H NMR (DMSO-d₆) δ: 11.56 (br. s., 1H), 8.94 (d, J=2.4 Hz, 1H), 8.39 (d,J=8.0 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.95 (d, J=0.8 Hz, 1H), 7.74 (dd,J=1.6 Hz, 1.6 Hz, 1H), 7.58-7.40 (m, 6H), 2.80 (m, 1H), 2.34 (s, 3H),1.81-1.60 (m, 8H), 1.30-1.23 (m, 2H). LC-MS: m/z 435.2 (M+H)⁺.

Compound 278

Step A:5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a suspension of5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 319, 500 mg, 1.126 mmol) in DCM (3 mL) cooled in ice-bath wasadded SOCl₂ (670 mg, 5.631 mmol) dropwise. The resultant mixture wasthen stirred at room temperature overnight. The suspension was filtered,washed with ethyl acetate, and dried under vacuum. The residue waspurified by prep-TLC (DCM:MeOH=20:1) to get5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(300 mg). LC-MS: m/z 463.1 (M+H)⁺.

Step B: Compound 278:5-((methylamino)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(150 mg, 0.324 mmol) in methylamine (2.0 M in MeOH, 5 mL) was stirred at50° C. overnight. Water (10 mL) was added to quench the reaction. Theresultant mixture was concentrated to to get the title compound.

¹H NMR (400 MHz, TFA) δ: 9.26-9.48 (m, 2H), 8.57-8.76 (m, 2H), 8.42 (d,J=8.60 Hz, 1H), 8.35 (dd, J=8.33, 5.64 Hz, 1H), 7.64-7.81 (m, 6H),7.55-7.62 (m, 2H), 7.51 (d, J=7.25 Hz, 2H), 4.80 (br. s., 2H), 2.95 (s,3H). LC-MS: m/z 458.1 (M+H)⁺.

Compound 279

Step A:3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84mmol) and dimethyl 2-(4-methoxyphenyl)malonate (240 mg, 1.00 mmol) intributylamine (5 ml) was heated to 180° C. for 1 h under N₂ protection.The mixture was cooled to the RT and stirred with petroleum ether to getthe desired product.

¹H NMR (DMSO-d₆) δ: 12.05 (br. s., 1H), 7.56-6.50 (m, 9H), 5.67 (s, 1H),3.73 (s, 3H), 2.09 (br. s., 2H), 1.91 (br. s., 2H), 1.58 (br. s., 4H).LC-MS: m/z 414.0 (M+H)⁺.

Compound 280

Step A: methyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate

To a solution of methyl 1H-pyrazole-3-carboxylate (1 g, 7.9 mmol) in THF(30 mL) was added sodium hydride (380 mg, 60% dispersion in mineral oil,9.5 mmol) at 0° C. After the mixture was stirred at 0° C. for 30 min,(2-(chloromethoxy)ethyl)trimethylsilane (1.6 g, 9.5 mmol) was addeddropwise. Then the mixture was stirred at r.t. overnight. The mixturewas diluted with EA (30 mL) and quenched with saturated NH₄Cl. Theorganic phase was separated and washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue was purified by flashchromatography to afford the intermediate 2 as a white solid (1.1 g, 54%yield).

¹H NMR (CHLOROFORM-d) δ: 7.55 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H),5.86 (s, 2H), 3.90 (s, 3H), 3.59 (t, J=8.0 Hz, 2H), 0.90 (t, J=8.0 Hz,2H), −0.04 (s, 9H). LC-MS: m/z 257.1 (M+H)⁺.

Step B:3-oxo-2-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propanenitrile

To the mixture of Intermediate 2 (600 mg, 2.3 mmol) and2-phenylacetonitrile (330 mg, 2.8 mmol) in THF (20 mL) was added NaHMDS(2.0 mol/L in THF, 1.4 mL) dropwise at 0° C. The mixture was kept at 0°C. for 30 min, and then stirred at r.t. overnight. The mixture wasdiluted with EA (20 mL) and quenched with saturated NH₄Cl. The organicphase was separated and washed with brine, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified by flashchromatography to afford the intermediate 3 as a light yellow solid (200mg, 25% yield).

¹H NMR (DMSO-d₆) δ: 12.41 (br. s., 1H), 7.73-7.78 (m, 2H), 7.66 (d,J=1.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 6.77 (d,J=1.8 Hz, 1H), 5.49 (s, 2H), 3.45 (t, J=8.0 Hz, 2H), 0.81 (t, J=8.0 Hz,2H), −0.10 (s, 9H). LC-MS: m/z 342.1 (M+H)⁺.

Step C:4-phenyl-1′-((2-(trimethylsilyl)ethoxy)methyl)-1H,1′H-[3,3′-bipyrazol]-5-amine

The mixture of Intermediate 3 (200 mg, 0.6 mmol) and hydrazine hydrate(59 mg, 1.2 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (20 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the the water phase was extracted with EA (10mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo to afford the intermediate 4as a yellow solid (200 mg, 96% yield) which was used to the next stepwithout purification. LC-MS: m/z 356.1 (M+H)⁺.

Step D:5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 4 (200 mg, 0.56 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate 8 (205 mg, 0.85 mmol) in AcOH (8 mL)was stirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (15 mL) and neutralized with10% NaHCO₃. The organic phase was separated and the water phase wasextracted with EA (15 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to affordthe intermediate 5 as a yellow solid (200 mg, 65% yield) which was usedto the next step without purification. LC-MS: m/z 549.2 (M+H)⁺.

Step E:5-methyl-3-phenyl-2-(1H-pyrazol-3-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 5 (200 mg, 0.4 mmol) in DCM (10 mL) wasadded trifluoroacetic acid (0.5 mL). The mixture was stirred at r.t.overnight. The mixture was concentrated in vacuo and then dissolved inDCM (10 mL), washed with 10% NaHCO₃ and brined, dried over anhydrousNa₂SO₄, and concentrated in vacuo to afford the desired product 6.

¹H NMR (DMSO-d₆) δ: 12.84 (br. s., 1H), 8.91 (d, J=2.6 Hz, 1H), 8.37 (d,J=8.0 Hz, 1H), 8.17 (br. s., 1H), 8.05 (d, J=8.6 Hz, 1H), 7.94 (s, 1H),7.75 (d, J=8.6 Hz, 1H), 7.40-7.63 (m, 6H), 7.36 (d, J=7.2 Hz, 1H), 6.18(br. s., 1H), 2.22 (s, 3H). LC-MS: m/z 419.0 (M+H)⁺.

Compound 281

Step A: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate

To a mixture of methyl 2-(quinolin-6-yl)acetate (40.2 g, 0.2 mol) andHMPA (7.2 g, 0.02 mol) in THF was added LDA (2M in THF; 100 mL, 0.2 mol)over 20 min at −78° C. The mixture was stirring for 1 hour at −78° C.,2-(benzyloxy)acetyl chloride (36.8 g, 0.2 mol) was added dropwise with afunnel. The mixture was warmed up to room temperature overnight.Saturated NH₄Cl aqueous solution was added. The resultant mixture wasextracted with DCM (3*50 mL). The combined organic layers were washedwith saturated NaCl (50 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel column(PE/EtOAc=20/1) to give the title compound (38 g, 58%) as a brown oil.

Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate

Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.2 g, 3.4 mmol)and 3,4-diphenyl-1H-pyrazol-5-amine (545 mg, 3.4 mmol) were dissolved inAcOH (10 mL). The mixture was warmed up to 95° C. for 4 h. After coolingto room temperature, the solids were collected by filtration, wash withEtOAc, and dried under vacuum to give methyl4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.05 g, 67% yield) as awhite solid. LC-MS: m/z 459.1 (M+H)⁺.

Step C:5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate(900 mg, 1.97 mmol) and Cs₂CO₃ (1.38 g, 4.25 mmol) in DMF (10 mL) wasadded MeI (416 mg, 2.95 mmol). The mixture was then stirred at rtovernight. The mixture was poured into water (100 mL) and filtered. Thefilter cake was washed with MeOH to give5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(900 mg) as a white solid. LC-MS: m/z 473.0 (M+H)⁺.

Step D:5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(900 mg, 1.9 mmol) in DMF (10 mL) was added NBS (374 mg, 2.1 mmol). Thereaction mixture was then stirred at room temperature for 2 h. Themixture was poured into water (50 mL) and filtered to give5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(900 mg, yield 86%) as a white solid. LC-MS: m/z 551.0 (M+H)⁺.

Step E:5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(800 mg, 1.45 mmol), phenylboronic acid (230 mg, 1.89 mmol), Pd₁₁₈ (188mg, 0.29 mmol) and K₂CO₃ (496 mg, 3.64 mmol) in 1.4-dioxane (6 mL) andH₂O (0.5 mL) was stirred at 100° C. for 12 h under N₂ atmosphere. Thereaction mixture was then cooled to r.t. and filtered. The filtrate wasconcentrated in vacuo and purified by flash column chromatography silicagel to obtain5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(700 mg, 88% yield). LC-MS: m/z 549.0 (M+H)⁺.

Step F: Compound 281:5-(hydroxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(700 mg, 1.28 mmol) in dry DCM (5 mL) was added dropwise BBr₃ (1M inDCM, 2.56 mL, 2.56 mmol) at 0° C. After addition, the mixture wasstirred at rt for 2 h. The mixture was quenched by careful adding ofice-water and extracted with EA. The combined organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (br. s., 1H), 8.42 (d, J=7.79 Hz, 1H),8.10 (d, J=8.87 Hz, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.76 (dd, J=8.60, 1.88Hz, 1H), 7.60 (dd, J=8.33, 4.03 Hz, 1H), 7.48 (s, 5H), 7.36-7.42 (m,2H), 7.25-7.33 (m, 3H), 4.37 (br. s., 2H), 3.49 (s, 3H). LC-MS: m/z459.0 (M+H)⁺

Compound 282

Step A: 3-iodocyclohex-2-enone

A mixture of PPh₃ (25 g, 96.5 mmol) and 12 (24 g, 94.8 mmol) inacetonitrile (400 mL) was stirred at r.t. for 2 h, then Et₃N (14.4 mL,98.3 mmol) and cyclohexane-1,3-dione (10.0 g, 86.2 mmol) were added. Themixture was stirred at r.t. overnight. The mixture was concentrated invacuo, and the residue was purified by chromatography to afford thetitle compound 2 as a yellow solid (4.0 g, 21% yield). LC-MS: m/z 222.9(M+H)⁺.

Step B: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone

A suspension of Intermediate 2 (2.0 g, 9 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.6 g, 18mmol), KOAc (2.7 g, 27 mmol) and Pd(dppf)Cl₂ (0.6 g, 0.9 mmol) in1,4-dioxane (50 mL) was stirred at 90° C. overnight. The mixture wasfiltered through celite and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography to afford the titlecompound 3 as a yellow solid (1.0 g, 50% yield). LC-MS: m/z 223.1(M+H)⁺.

Step C:5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of methyl 3-oxo-2-(quinolin-6-yl)butanoate (2.0 g, 8.2mmol) and 3-phenyl-1H-pyrazol-5-amine (1.0 g, 6.3 mmol) in 1,4-dioxane(10 mL) and AcOH (2 mL) was refluxed for 16 hours under N₂ protection.The mixture was cooled to the room temperature, concentrated, andneutralized with saturated NaHCO₃ solution until pH=7. The precipitatewas collected by filtration, washed with petroleum ether and dried toafford the title compound 5 as a white solid (600 mg, 27% yield).

¹H NMR (DMSO-d₆) δ: 12.56 (br. s., 1H), 8.94 (dd, J=4.25, 1.61 Hz, 1H),8.39 (d, J=7.63 Hz, 1H), 7.99-8.10 (m, 3H), 7.96 (d, J=1.76 Hz, 1H),7.75 (dd, J=8.66, 1.91 Hz, 1H), 7.57 (dd, J=8.36, 4.25 Hz, 1H),7.46-7.53 (m, 2H), 7.40-7.46 (m, 1H), 6.67 (s, 1H), 2.26 (s, 3H). LC-MS:m/z 353.1 (M+H)⁺.

Step D:5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 5 (500 mg, 1.42 mmol) and K₂CO₃ (393 mg,2.84 mmol) in DMF (15 ml) at ambient temperature was added(2-(chloromethoxy)ethyl)trimethylsilane (473 mg, 2.84 mmol) dropwise.The mixture was stirred for 10 min at ambient temperature and heated to100° C. overnight. The mixture was cooled to the room temperature,washed with saturated sodium hydrogen carbonate solution, and extractedwith DCM (2*30 mL). The combined organic layers were washed with brine(3*20 ml), dried over anhydrous sodium sulfate, and concentratedinvacuo. The residue was purified by silica gel column, eluting withDCM/MeOH (30/1 to 10/1), to obtain the title compound 6 as a white solid(350 mg, 51% yield). LC-MS: m/z 483.1 (M+H)⁺.

Step E:3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 6 (350 mg, 0.725 mmol) in DCM (5 ml) atambient temperature was added N-Bromosuccinimide (163 mg, 0.92 mmol).The resultant mixture was stirred for 3 hours at ambient temperature,washed with water, and extracted with DCM (20 mL). The combined organiclayers were washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=20/1) to obtain the title compound 7 as a yellow solid (250mg, 61% yield). LC-MS: m/z 561.1 (M+H)⁺.

Step F:5-methyl-3-(3-oxocyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 7 (600 mg, 1.1 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (800 mg,3.6 mmol), Pd(dppf)Cl₂ (80 mg, 0.1 mmol) and Cs₂CO₃ (1.4 g, 4.3 mmol) in1,4-dioxane/H₂O (30 mL/5 mL) was refluxed for 4 h. The mixture wascooled to r.t. and filtered through celite, the filtrate was dilutedwith H₂O (10 mL) and extracted with EA (3*30 mL). The extracts waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography (DCM/MeOH=20/1)to afford the title compound 8 as a yellow solid (300 mg, 49% yield).LC-MS: m/z 577.2 (M+H)⁺.

Step G:5-methyl-3-(3-oxocyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of intermediate 8 (100 mg, 0.2 mmol) in DCM (10 mL) wasadded TFA (1 mL). The mixture was stirred at r.t. overnight. The mixturewas concentrated in vacuo. The residue was dissolved in EA (10 mL) andneutralized with 10% NaHCO₃. The organic phase was separated and thewater phase was extracted with EA (3*5 mL). The combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by prep-TLC to get the title compound 9as an orange solid (30 mg, 39% yield). LC-MS: m/z 447.1 (M+H)⁺.

Step H:3-(3-hydroxycyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of intermediate 9 (30 mg, 0.07 mmol) and Cerium (III)chloride heptahydrate (43 mg, 0.1 mmol) in MeOH (3 mL) was added Sodiumborohydride (5 mg, 0.1 mmol). The mixture was stirred at r.t. for 2 hand quenched with H₂O (0.5 mL). The mixture was evaporated. The residuewas dissolved in EA (10 mL), washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to get the title compound 10.

¹H NMR (METHANOL-d₄) δ: 8.83 (d, J=3.2 Hz, 1H), 8.39 (d, J=7.4 Hz, 1H),8.07 (d, J=8.6 Hz, 1H), 7.95 (br. s., 1H), 7.81 (br. s., 3H), 7.55 (dd,J=8.2, 4.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.38 (d, J=7.4 Hz, 2H), 5.97(d, J=2.4 Hz, 1H), 4.32-4.38 (m, 1H), 2.29 (s, 3H), 2.05-2.15 (m, 2H),1.92-1.98 (m, 1H), 1.80-1.89 (m, 1H), 1.62-1.75 (m, 2H). LC-MS: m/z449.1 (M+H)⁺.

Compound 283

Step A:5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(Synthesized in Scheme of Compound 101, 300 mg, 0.7 mmol) and(4-methoxyphenyl)methanamine (3 mL) was stirred at 180° C. for 40 minsin a microwave reactor. The mixture was cooled and derectly purified byreverse phase column (MeOH/H₂O=0-50% 30 mins, 50%-50% 30 mins, 50%-100%30 mins) to get crude product (600 mg) which was directly used to thenext step without further purification. LC-MS: m/z 529.2 (M+H)⁺.

Step B:5-amino-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo1,5-a]pyrimidin-7(4H)-one (600 mg, 1.07 mmol) in DCM (5 mL) and TFA (5mL) was stirred at 60° C. for 2 h. The mixture was concentrated,basified with aq.Na₂CO₃ solution to pH=8, and extracted with DCM (10mL*3). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to dryness. The residue was purified by reversephase column (MeOH/H₂O=0-100% 50 mins) to afford the desired product5-amino-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(480 mg, 80% purity) as a brown solid. LC-MS: m/z 409.2 (M+H)⁺.

Step C: tert-butyl(2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-oxoethyl)carbamate

To a solution of5-amino-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.245 mmol) in pyridine (3 mL) was added2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)acetate (333 mg,1.22 mmol) and DMAP (cat.). The mixture was stirred at 120° C. for 45mins through microwave irradiation. The mixture was concentrated invacuo to dryness. The residue was separated between HCl (1M, 10 mL) andDCM (30 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated in vacuo to dryness. The residue was purified byPrep-TLC (DCM/MeOH=50/1) to afford the desired product tert-butyl(2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amio)-2-oxoethyl)carbamate(20 mg, 14.5% yield) as a white solid. LC-MS: m/z 565.2 (M+H)⁺.

Step D: Compound 283:2-amino-N-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide

The solution of tert-butyl(2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-2-oxoethyl)carbamate(20 mg, 0.035 mmol) in 4M HCl in 1.4-dioxane was stirred r.t. for 2 h.The mixture was concentrated to obtain2-amino-N-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazlo[1,5-a]pyrimidin-5-yl)acetamide.

¹H NMR (DMSO-d₆) δ: 7.61-7.42 (m, 5H), 7.42-7.25 (m, 9H), 7.00 (d, J=8.3Hz, 2H), 3.82 (s, 3H), 3.62-3.59 (m, 2H). LC-MS: m/z 466.0 (M+H)⁺.

Compound 285

Step A:N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-5-methyl-1,3,4-thiadiazol-2-amine

A mixture of Intermediate 1 (Synthesized in Scheme of Compound 101, 200mg, 0.45 mmol), 5-methyl-1,3,4-thiadiazol-2-amine (102 mg, 0.9 mmol, 2eq.), Pd(OAc)₂ (10 mg, 0.045 mmol, 0.1 eq.), Xantphos (52 mg, 0.09 mmol,0.2 eq.) and Cs₂CO₃ (293 mg, 0.9 mmol, 2 eq.) in 1.4-dioxane (3 mL) washeated at 100° C. for 3 h under N₂ atmosphere. The mixture was filteredthrough celite and the filtrate was concentrated in vacuo. The residuewas purified by flash chromatography to afford the Intermediate 2 as ayellow solid (200 mg, 85% yield). LC-MS: m/z 520.7 (M+H)⁺.

Step B: Compound 285:6-(4-methoxyphenyl)-5-((5-methyl-1,3,4-thiadiazol-2-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution ofN-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-5-methyl-1,3,4-thiadiazol-2-amine(180 mg, 0.346 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred atr.t. for 10 h to afford the title compound 3.

¹H NMR (DMSO-d₆) δ: 7.53 (br. s., 3H), 7.49-7.37 (m, 7H), 7.32 (d, J=8.3Hz, 3H), 7.06 (d, J=8.3 Hz, 2H), 3.83 (s, 3H), 2.55 (br. s., 3H). LC-MS:m/z 507.2 (M+H)⁺.

Compound 286

Step A:5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(Synthesized in Scheme of Compound 101, 200 mg, 0.45 mmol), potassiumt-butoxide (50 mg, 0.45 mmol) in dioxane was stirred at 100° C. for 2 h.The mixture was concentrated to give the crude product (200 mg) whichwas used to the next step without further purification. LC-MS: m/z 428.1(M+H)⁺.

Step B: Compound 286:5-((2-hydroxyethyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.23 mmol) and 2-aminoethanol (3 mL) was stirred at 170° C. for4 h under microwave irradiation in a sealed tube to get5-((2-hydroxyethyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.28 (br. s., 5H), 7.22 (d, J=7.25 Hz, 5H),7.06-7.17 (m, 3H), 6.96 (d, J=7.79 Hz, 2H), 3.81 (s, 3H), 3.66 (br. s.,2H), 3.43 (br. s., 2H). LC-MS: m/z 453.2 (M+H)⁺.

Compound 287

Step A: ethyl3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazole-1-carboxylate

To a solution of5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 182, 50 mg, 0.1 mmol) in DMF (5 mL) was added sodium hydride(13 mg, 60% dispersion in mineral oil, 0.3 mmol) at 0° C. Ethylchloroformate (24 mg, 0.2 mmol) was added dropwise after the mixture wasstirred at 0° C. for 30 min. Then the mixture was stirred at r.t.overnight. The mixture was poured into water (10 mL) and extracted withDCM (3*5 mL), the combined organic phase was washed with brine, driedover anhydrous Na₂SO₄, and concentrated in vacuo to afford the desiredproduct.

¹H NMR (DMSO-d₆ & TFA-d) δ: 8.22 (d, J=3.0 Hz, 1H), 7.43-7.50 (m, 4H),7.34-7.41 (m, 6H), 7.31 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H),6.36-6.45 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H).LC-MS: m/z 547.1 (M+H)⁺.

Compound 288

Step E:5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of Intermediate 5 (200 mg, 0.4 mmol, synthesized in schemeof Compound 249),2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94 mg,0.5 mmol, 1.2 eq), Pdius (48 mg, 0.07 mmol, 0.2 eq) and K₂CO₃ (103 mg,0.7 mmol, 2.0 eq) in 1.4-dioxane (5 ml) and H₂O (0.3 ml) was stirred at90° C. for 4 h under N₂ atmosphere. The reaction mixture was then cooledto r.t. and filtered. The filtrate was concentrated in vacuo andpurified by flash column chromatography silica gel (PE/EA 2:1-1:2) toobtain Intermediate 6 (39 mg, 20% yield). LC-MS: m/z 532.0 (M+H)⁺

Step F:3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 6 (29 mg, 0.05 mmol) in dry DCM (3 mL) wasadded dropwise BCl₃ (1 mol/L in DCM, 0.5 mL) at 0° C. After addition,the mixture was stirred at r.t. for 3 h. The mixture was quenched byice-water (3 mL) and extracted with DCM (3*5 mL). The combined organicphase was washed with water and brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound 7.

¹H NMR (DMSO-d₆) δ: 7.82 (d, J=7.0 Hz, 2H), 7.39-7.50 (m, 3H), 7.25 (d,J=8.4 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 5.92 (br. s., 1H), 5.69 (t, J=4.8Hz, 1H), 4.36 (d, J=4.6 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 2.20 (br.s., 2H), 2.12 (br. s., 2H), 1.66 (br. s., 4H). LC-MS: m/z 442.2 (M+H)⁺.

Compound 290

Step A: Dimethyl 2-(4-methoxyphenyl)malonate

To a solution of t-BuOK (7.4 g, 0.066 mol) in dimethyl carbonate (60 mL)was added dropwise methyl 2-(4-methoxyphenyl)acetate (6 g, 0.033 mol) at0° C. After addition, the mixture was allowed to warm to roomtemperature and stirred for 0.5 h. The mixture was then heated to 80° C.overnight. The suspension was diluted with EtOAc (200 mL), washed withwater and brine, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: EtOAc/PE=1/10) to afford thedesired product (5.7 g, 0.024 mol, yield 72.7%).

¹H NMR (CDCl₃) δ: 7.33 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 4.62(s, 1H), 3.82 (s, 3H), 3.77 (s, 6H).

Step B:5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (5.64 g, 0.024 mol) anddimethyl-2-(4-methoxyphenyl)-malonate 2 (5.7 g, 0.024 mol) in xylene(350 mL) was refluxed for 18 h to afford the title compound.

¹H NMR (DMSO-d₆) δ: 11.57 (br. s, 1H), 7.26-7.49 (m, 12H), 6.90-6.99 (m,2H), 3.78 (s, 3H). LC-MS: m/z 410.2 (M+H)⁺.

Compound 291

Step A: Compound 291:3-cyclohexenyl-1-(methoxymethyl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(1H)-one

A mixture of3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 212, 100 mg, 0.243 mmol), chloro(methoxy)methane (21.4 mg,0.268 mmol) and Cs₂CO₃ (159 mg, 0.486 mmol) in DMSO (5 mL) was stirredat room temperature for 5 days. The mixture was poured into water (20mL) and extracted with EtOAc (3*20 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to obtain the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54-7.64 (m, 5H), 7.21-7.27 (m, 2H), 6.99(m, J=8.85 Hz, 2H), 5.88 (br. s., 1H), 5.65 (s, 2H), 3.80 (s, 3H), 2.96(s, 3H), 2.21 (s, 3H), 2.14 (br. s., 2H), 2.01-2.08 (m, 2H), 1.51-1.64(m, 4H). LC-MS: m/z 456.1 (M+H)⁺.

Compound 292

Step A: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate

A mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl) acetate (4.3 g, 20.5mmol), ((2-bromoethoxy)methyl)benzene (7.88 g, 36.8 mmol), potassiumcarbonate (5.66 g, 41 mmol) in N,N-dimethylformamide (50 mL) was heatedto 80° C. for 18 h. The mixture was cooled to room temperature, pouredinto water (100 mL), and extracted with ethyl acetate (100 mL) threetimes. The combined organic phase was washed with brine, dried oversodium sulfate and evaporated to dryness. The crude mixture was purifiedby column chromatography (ethyl acetate:petroleumether=1:5) to affordethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate (3.8 g, 54%yield) as a colorless oil.

Step B: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate

To a solution of ethyl2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate (690 mg, 2 mmol) intetrahydrofuran (10 mL) was added lithium diisopropylamide (2N, 1 mL, 2mmol) at −78° C. under nitrogen atmosphere dropwise. The mixture wasstirred at the same temperature for 1 h. Acetyl chloride (156 mg, 2mmol) was added into the mixture at −78° C. slowly. After addition, themixture was stirred at −78° C. for 1 h and then warmed slowly to roomtemperature overnight. The mixture was quenched by adding aqueousammonium chloride to pH 6-7 and extracted with ethyl acetate (20 mL)three times. The combined organic phase was washed with brine, driedover sodium sulfate and evaporated to dryness. The crude was purified bycolumn chromatography on silica gel (ethyl acetate:petroleum ether=1:5)to afford ethyl2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 38%yield) as a colorless oil. LC-MS: m/z 387.2 (M+H)⁺.

Step C:6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]yrimidin-7(4H)-one

A mixture of ethyl2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg,0.725 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (170 mg, 0.725 mmol) inacetic acid (5 mL) was heated to reflux for 2 h. The mixture wasevaporated to remove acetic acid. The residue was purified by columnchromatography (methanol:dichloromethane=1:20) to afford6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]yrimidin-7(4H)-one(120 mg, 30% yield) as a yellow solid. LC-MS: m/z 558.2 (M+H)⁺.

Step D:6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.18 mmol) in DCM (10 mL) was added 1M BBr₃(0.5 mL) in DCMdropwise at 0° C., after addition, the mixture was stirred at roomtemperature for 1 h. MeOH (5 mL) was added carefully to quench thereaction. Then the mixture was evaporated, the residue was purified byprep-TLC (DCM/MeOH=100:10) to obtain the6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(60 mg) as a white solid. LC-MS: m/z 468.2 (M+H)⁺.

Step E:2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl4-methylbenzenesulfonate

A mixture of6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.427 mmol), TsCl (97 mg, 0.512 mmol), DMAP (52 mg, 0.427mmol), Et₃N (130 mg, 1.281 mmol) in DCM (5 mL) was stirred at 50° C. for18 h. The mixture was quenched by addition of water and extracted withDCM (2*20 mL). The combined organic layers were washed with brine andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM/MeOH=100:5) to obtain the2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl4-methylbenzenesulfonate (150 mg) as a white solid. LC-MS: m/z 622.1(M+H)⁺.

Step F:6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl4-methylbenzenesulfonate (150 mg, 0.241 mmol) and dimethylamine (30% inH₂O, 1 mL) in THF (5 mL) in a seal tube was stirred at 70° C. overnight.The reaction mixture was cooled to room temperature and evaporated underreduced pressure to get the crude6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(140 mg) as an oil, which was used in the next step without furtherpurification. LC-MS: m/z 495.0 (M+H)⁺.

Step G: Compound 292:6-(3-(2-(dimethylamino)ethoxy)-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(140 mg, 0.225 mmol) in DCM (4 mL) was added BBr₃ (1M in DCM, 1 mL)dropwise. The mixture was then stirred at room temperature for 2 h. Themixture was quenched by addition of MeOH and concentrated under reducedpressure to obtain6-(3-(2-(dimethylamino)ethoxy)-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.38-7.62 (m, 10H), 7.17 (br. s., 1H),7.02 (br. s., 2H), 4.44 (br. s., 2H), 3.66 (br. s., 2H), 3.07 (s, 6H),2.33 (s, 3H). LC-MS: m/z 481.1 (M+H)⁺.

Compound 294

Step A: (S)-chloromethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate

A mixture of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1g, 4.6 mmol), chloromethyl sulfochloridate (912 mg, 5.53 mmol),NaHCO₃(1.54 g, 18.4 mmol) in DCM (5 mL) and H₂O (5 mL) was stirred atroom temperature overnight. Water (20 mL) was added. The mixture wasextracted with DCM (3*20 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to get the title compound (800 mg) as a colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ: 5.90 (d, J=5.91 Hz, 1H), 5.64 (d,J=6.18 Hz, 1H), 5.00 (d, J=8.06 Hz, 1H), 4.29 (dd, J=8.87, 4.57 Hz, 1H),2.21 (dd, J=12.09, 6.45 Hz, 1H), 1.02 (d, J=6.98 Hz, 3H), 0.94 (d,J=6.98 Hz, 3H).

Step B:(S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl2-(tert-butoxycarbonylamino)-3-methylbutanoate

To a mixture of3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 240, 200 mg, 0.504 mmol), NaI (76 mg, 0.504 mmol), Cs₂CO₃ (330mg, 1.0 mmol) in DMF (5 mL) was added (S)-chloromethyl2-(tert-butoxycarbonylamino)-3-methylbutanoate (200 mg, 0.755 mmol). Themixture was stirred at room temperature for 1 h. Then the mixture wasquenched by addition of water (20 mL) and extracted with EtOAc (2*20mL). The combined organic layers were concentrated. The residue waspurified by column chromatography on silica gel (eluting PE/EA=2:1) togive the desired product (150 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (s, 1H), 7.78 (d, J=7.25 Hz, 2H),7.44-7.53 (m, 3H), 7.35-7.44 (m, 3H), 7.14 (d, J=8.33 Hz, 2H), 5.85 (br.s., 1H), 4.05-4.11 (m, 1H), 2.25 (s, 3H), 2.19-2.23 (m, 3H), 2.06 (br.s., 2H), 1.71 (br. s., 4H), 1.44 (s, 9H), 1.03 (d, J=6.72 Hz, 6H).LC-MS: m/z 597.2 (M+H)⁺.

Step C: Compound 294:(S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl2-amino-3-methylbutanoate

To a solution of(S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl2-(tert-butoxycarbonylamino)-3-methylbutanoate (150 mg, 0.251 mmol) inDCM (5 mL) was added TFA (2 mL). Then the mixture was stirred at roomtemperature for 2 h, and evaporated under reduced pressure to get thetitle compound.

¹H NMR (DMSO-d₆+TFA) δ: 11.79 (s, 1H), 8.59 (br. s., 3H), 7.75-7.82 (m,2H), 7.39-7.51 (m, 5H), 7.23-7.29 (m, 2H), 5.86 (br. s., 1H), 4.29 (br.s., 1H), 2.32-2.42 (m, 1H), 2.26 (s, 3H), 2.22 (br. s., 2H), 2.07 (br.s., 2H), 1.71 (br. s., 4H), 1.15 (d, J=6.98 Hz, 3H), 1.12 (d, J=6.98 Hz,3H). LC-MS: m/z 497.1 (M+H)⁺.

Compound 295

Step A: methyl 2-(4-methoxyphenyl)-3-oxobutanoate

To a solution of methyl 2-(4-methoxyphenyl)acetate (900 mg, 5.0 mmol))in THF (15 mL) was added slowly LDA (2.5 mL, 2 mmol/mL in THF) at −30°C. Then acetyl chloride (500 mg, 6.5 mmol) was added slowly. Thereaction mixture was stirred for 30 mins at −30° C. and allowed to roomtemperature for 1 h. The mixture was poured into water, extracted overethyl acetate, dried over anhydrous Na₂SO₄, filtered, and concentratedto give the crude product (800 mg) as a yellow liquid, which was useddirectly to the next step without further purification.

Step B:3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The solution of 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (200mg, 0.84 mmol) and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (371.5 mg,1.67 mmol) in AcOH (5 mL) was stirred at 100° C. for 1 hour. Aftercooling to room temperature, solvent was removed by vacuum, andsaturated NaHCO₃ was added till pH>7. The precipitate was filtered,washed with water (6 mL) and MeOH (0.5 mL) to obtain3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(260 mg) as a white solid.

¹H NMR (DMSO-d₆) δ: 11.62 (s, 1H), 7.72-7.85 (m, 2H), 7.34-7.55 (m, 3H),7.19-7.31 (m, 2H), 6.93-7.07 (m, 2H), 5.84 (br. s., 1H), 3.81 (s, 3H),2.17-2.32 (m, 5H), 1.98-2.12 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z412.3 (M+H)⁺.

Step C:3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.118 mmol) in CH₂Cl₂ (1 mL) was added slowly BBr₃ (3 mL, 1mmol/mL in CH₂Cl₂) at 0° C. And then the reaction mixture was stirredovernight. The reaction was quenched with ice water at −10° C. andconcentrated. The residue was purified by prep-HPLC to obtain the titlecompound (15 mg) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.76 (d, J=7.02 Hz, 2H), 7.30-7.52 (m, 3H), 7.09 (m,J=7.93 Hz, 2H), 6.82 (m, J=7.93 Hz, 2H), 5.83 (br. s., 1H), 2.21 (br.s., 3H), 2.18 (br. s., 2H), 2.03 (br. s., 2H), 1.67 (br. s., 4H). LC-MS:m/z 398.0 (M+H)⁺.

Step D: dibenzyl4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenylphosphate

To a solution of3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.1 mmol) in DMF (5 mL) was added dibenzyl chloromethylphosphate (50 mg, 0.15 mmol) in DMF (1 mL) and Cs₂CO₃ (100 mg, 0.3 mmol)at room temperature. The mixture was warmed to 80° C. and stirredovernight. The reaction mixture was cooled to room temperature, thenpoured into water (20 mL), and extracted with EtOAc (3*20 mL). Thecombined organic layers were washed with water (2*20 mL) and brine (20mL), and then concentrated under reduced pressure. The residue waspurified by prep TLC, eluting with EA/DCM=2:3, to get the title compound(20 mg) as a white solid. LC-MS: m/z 658.1 (M+H)⁺.

Step E: Compound 295:4-(3-(cyclohex-1-en-1-yl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyldihydrogen phosphate

To a solution of dibenzyl4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenylphosphate (20 mg, 0.03 mmol) in MeOH (2 mL) was added Pd/C (3 mg). Themixture was stirred at room temperature under H₂ for 10 min andfiltered. The filtrate was concentrated to afford the title compound (12mg).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.70 (br. s., 1H), 7.78 (d, J=7.25 Hz,2H), 7.42-7.49 (m, 2H), 7.36-7.42 (m, 1H), 7.19 (br. s., 2H), 7.11 (d,J=8.06 Hz, 2H), 5.82 (br. s., 1H), 2.21 (br. s., 5H), 2.08 (br. s., 2H),1.69 (br. s., 4H). LC-MS: m/z 477.9 (M+H)⁺.

Compound 296

Step A: di-tert-butyl(4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)methylphosphate

To a solution of3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 240, 300 mg, 0.75 mmol) in DMF (10 mL) was added NaH (60%dispersion in mineral oil, 75.6 mg, 1.89 mmol) and TBAB (36 mg, 0.15mmol) at 0° C. for 5 min. Then di-tert-butyl chloromethyl phosphate (250mg, 1.13 mmol) in DMF (5 mL) was added. The mixture was warmed to roomtemperature and stirred for 2 h. The reaction mixture was poured intowater (20 mL), extracted with DCM (3*20 mL). The combined organic layerswere washed with water (2*20 mL) and brine (20 mL), and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (ethyl acetate:DCM=1:3) to get the titlecompound (120 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.66 (s, 1H), 7.77 (d, J=7.02 Hz, 2H),7.44-7.50 (m, 2H), 7.41 (d, J=7.32 Hz, 1H), 7.29 (m, J=8.54 Hz, 2H),7.13 (m, J=8.54 Hz, 2H), 5.84 (br. s., 1H), 5.67 (d, J=12.21 Hz, 2H),2.22 (s, 5H), 2.06 (br. s., 2H), 1.70 (br. s., 4H), 1.41 (s, 18H).LC-MS: m/z 620.1 (M+H)⁺.

Step B: Compound 296:(4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)methyldihydrogen phosphate

To a solution of di-tert-butyl(4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)methylphosphate (110 mg, 0.177 mmol) in DCM (2 mL) was added TFA (1 mL). Themixture was stirred at room temperature under N₂ for 30 min. Thereaction mixture was filtered off. The filter cake was washed with etherand dried to get the title compound.

1H NMR (400 MHz, DMSO-d₆) δ: 11.65 (s, 1H), 7.73-7.83 (m, 2H), 7.44-7.50(m, 2H), 7.38-7.44 (m, 1H), 7.25-7.31 (m, 2H), 7.14 (m, J=8.86 Hz, 2H),5.85 (br. s., 1H), 5.62 (d, J=11.28 Hz, 2H), 2.24 (s, 3H), 2.22 (br. s.,2H), 2.06 (br. s., 2H), 1.71 (br. s., 4H). LC-MS: m/z 508.2 (M+H)+.

Compound 297

Step A₁:5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

A solution of3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 279, 47.0 g, 104 mmol) in phosphorusoxychloride (100 mL) was stirred at reflux for 16 hrs. The solvent wasremoved invacuo. The residue was added slowly to methanol (100 mL)cooled at 0° C. The precipitates were collected by filtration, washedwith methanol, and dried under reduced pressure to give5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(50 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 1.70 (d, J=4.57 Hz, 4H) 2.20 (br. s., 4H) 3.84 (s,4H) 5.87 (br. s., 1H) 7.10 (d, J=8.60 Hz, 2H) 7.36-7.56 (m, 5H) 7.82 (d,J=7.25 Hz, 2H). LC-MS: m/z 450.2 (M+H)⁺.

Step B₁:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(40 g, 88 mmol) in dichloromethane (400 ml) at 0° C. was added sodiummethoxide (30% in methanol, 80 g) dropwise. The resultant mixture wasstirred for 10 min at 0° C. The reaction was quenched by adding icewater (100 mL) and extracted with dichloromethane (200 mL) three times.The combined organic layers were washed with brine (200 ml), dried overanhydrous sodium sulfate, and concentrated invacuo. The residue wassuspended in MeOH (50 mL). The precipitates were collected byfiltration, washed with MeOH, and dried under reduced pressure to give5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(36 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 7.78-7.91 (m, 2H), 7.42-7.58 (m, 3H), 7.33-7.42 (m,J=8.9 Hz, 2H), 7.00-7.14 (m, J=8.9 Hz, 2H), 5.83 (br. s., 1H), 4.14 (s,3H), 3.84 (s, 3H), 2.20 (d, J=5.9 Hz, 4H), 1.61-1.77 (m, 4H). LC-MS: m/z446.1 (M+H)⁺.

Step A:3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(300 mg, 0.68 mmol), pyridin-4-amine (70 mg, 0.75 mmol), and palladiumdiacetate (15 mg, 0.068 mmol), Xantphos (79 mg, 0.136 mmol) and Cs₂CO₃(443 mg, 1.36 mmol) in 1,4-dioxane (20 mL) was heated at 110° C. for 2hours under nitrogen atmosphere through microwave irradiation. Themixture was filtered through celite, and the filtrate was concentratedin vacuo. The residue was purified by flash chromatography to afford thedesired product 2 (40 mg, 11.7% yield) as a light yellow solid. LC-MS:m/z 504.2 (M+H)⁺.

Step B: Compound 297:3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(40 mg, 0.0.8 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at r.t.for 2 hours. The mixture was concentrated at low temperature (<25° C.),and saturated NaHCO₃(8 mL) was added. The precipitate was filtered. Thefilter cake was suspended in DCM/MeOH (14 mL, 1:6), filtered and washedwith MeOH (2 mL) to obtain3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 8.32 (d, J=7.02 Hz, 2H), 7.81 (d, J=7.02 Hz, 2H),7.38-7.56 (m, 4H), 7.20-7.36 (m, 5H), 6.91 (d, J=8.85 Hz, 2H), 5.89 (br.s., 1H), 3.75 (s, 3H), 2.18 (br. s., 2H), 2.10 (br. s., 2H), 1.69 (br.s., 4H). LC-MS: m/z 490.1 (M+H)⁺.

Compound 298

Step A: isobutyl 2-cyclopropylacetate

A mixture of 2-cyclopropylacetic acid (1 g, 10 mmol),1-iodo-2-methylpropane (1.65 g, 12 mmol) and Cs₂CO₃ (6.5 g, 20 mmol) inDMF (50 mL) was stirred at 80° C. for 16 h. The mixture was pouredslowly into saturated NH₄Cl and extracted with EA (3*100 mL). Thecombined organic phase was washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography to afford the desired ethyl isobutyl2-cyclopropylacetate (500 mg) as a colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ: 3.82 (d, J=6.72 Hz, 2H), 2.23 (d, J=6.98Hz, 2H), 1.81-1.93 (m, 1H), 0.92-1.02 (m, 1H), 0.89 (d, J=6.72 Hz, 6H),0.43-0.51 (m, 2H), 0.11-0.17 (m, 2H).

Step B: isobutyl 2-cyclopropyl-3-oxobutanoate

To a solution of 2-cyclopropylacetate (500 mg, 3.2 mmol) in THF (10 mL)was added LDA (1.5 M in THF, 2.5 mL, 3.84 mmol) dropwise at −78° C. Themixture was stirred at −78° C. for 30 min, and acetyl chloride (326 mg,4.2 mmol) was added dropwise. Then the mixture was stirred at rt for 4h. The mixture was poured slowly into saturated NH₄Cl and extracted withEA (3*20 mL). The combined organic phase was washed with brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography to afford the desired isobutyl2-cyclopropyl-3-oxobutanoate (380 mg) as a brown oil.

Step C: Compound 298:6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 2-cyclopropyl-3-oxobutanoate (327 mg, 1.65 mmol) and3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (200 mg, 0.825 mmol) indioxane (5 mL) and water (1 mL) was stirred at 115° C. under microwaveirradiation for 2 h. The solvent was removed under reduced pressure togive6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (br. s., 1H), 8.10 (d, J=7.25 Hz,2H), 7.41-7.48 (m, 2H), 7.37 (d, J=7.25 Hz, 1H), 3.00-3.11 (m, 4H), 2.50(s, 3H), 1.63 (br. s., 4H), 1.56 (br. s., 2H), 1.42-1.50 (m, 1H),0.80-0.89 (m, 2H), 0.57-0.67 (m, 2H). LC-MS: m/z 349.6 (M+H)⁺.

Compound 299

Step A:5-methyl-2,6-diphenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (70 mg,0.29 mmol) and methyl 3-oxo-2-phenylbutanoate (120 mg, 0.58 mmol) inAcOH (2 ml) was refluxed for 30 min under N₂ protection. The mixture wascooled to the RT, concentrated, and neutralized with saturated sodiumhydrogen carbonate solution to adjust to pH=7 to obtain the desiredproduct.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 8.12 (t, J=4.0 Hz, 2H), 7.49-7.31 (m,8H), 3.08 (br. s., 4H), 2.26 (s, 3H), 1.67-1.50 (m, 6H). LC-MS: m/z485.2 (M+H)⁺.

Compound 300

Step A: isobutyl 2-cyclopentylacetate

A mixture of 2-cyclopentylacetic acid (1 g, 7.8 mmol),1-iodo-2-methylpropane (1.7 g, 9.36 mmol) and Cs₂CO₃ (5.1 g, 15.6 mmol)in DMF (40 mL) was stirred at 80° C. for 16 h. The mixture was pouredslowly into saturated NH₄Cl and extracted with EA (3*100 mL). Thecombined organic phase was washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography to afford the desired isobutyl 2-cyclopentylacetate(988 mg) as a colorless oil.

Step B: isobutyl 2-cyclopentyl-3-oxobutanoate

To a solution of 2-cyclopropylacetate (988 mg, 6.33 mmol) in THF (10 mL)was added LDA (1.5 M in THF, 4.6 mL, 6.96 mmol) dropwise at −78° C. Themixture was stirred at −78° C. for 30 min, and acetyl chloride (1.86 g,23.72 mmol) was added dropwise. Then the mixture was stirred at rt for 4h. The mixture was poured slowly into saturated NH₄Cl and extracted withEA (3*20 mL). The combined organic phase was washed with brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography to afford the desired isobutyl2-cyclopentyl-3-oxobutanoate (700 mg) as a colorless oil.

Step C: Compound 300:6-cyclopentyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

2-cyclopentyl-3-oxobutanoate (467 mg, 2.06 mmol) and3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (250 mg, 1.03 mmol) weredissolved in AcOH (10 mL). The mixture was warmed to 95° C. for 4 h.After cooling to room temperature, the solids were collected byfiltration and washed with EtOAc to afford6-cyclopentyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.98 (br. s., 1H), 8.06-8.17 (m, 2H),7.43-7.49 (m, 2H), 7.36-7.41 (m, 1H), 3.03-3.07 (m, 4H), 2.46 (s, 3H),1.92-2.05 (m, 3H), 1.84 (br. s., 2H), 1.54-1.74 (m, 10H). LC-MS: m/z377.6 (M+H)⁺.

Compound 301

Step A:6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 100 mg, 0.194 mmol) and(3-aminophenyl)boronic acid (53 mg, 0.386 mmol) in dioxane/H₂O (5 mL/1mL) was added1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogenatmosphere overnight. The reaction mixture was filtered and concentratedin vacuo. The residue was purified by column chromatography(methanol:dichloromethane=1/20) to afford5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(35 mg, 34.3% yield) as a white solid. LC-MS: m/z 530.1 (M+H)⁺.

Step B: Compound 301:6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-on(35 mg, 0.1 mmol) in CF₃COOH (2 mL) was heated to 60° C. for 3 h. Themixture was cooled to room temperature and concentrated in vacuo toafford6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.33 (br. s., 1H), 8.12 (d, J=7.25 Hz, 2H),7.44-7.50 (m, 2H), 7.41 (d, J=7.25 Hz, 1H), 7.06 (t, J=7.66 Hz, 1H),6.55 (d, J=8.60 Hz, 1H), 6.48 (s, 1H), 6.41 (d, J=7.52 Hz, 1H), 5.08(br. s., 2H), 3.09 (br. s., 4H), 2.25 (s, 3H), 1.66 (br. s., 4H), 1.59(br. s., 2H). LC-MS: m/z 400.5 (M+H)⁺.

Compound 302

Step A: ethyl 2-morpholino-3-oxobutanoate

To the solution of morpholine (0.95 g, 27 mmol) in CH₃CN (20 mL) andK₂CO₃ (3.01 g, 54 mmol) and added dropwise ethyl 2-chloro-3-oxobutanoate(2 g, 27 mmol) over 2 h. After addition, The mixture was concentratedand purified by silica gel chromatography (PE/EA=5/1) to get ethyl2-morpholino-3-oxobutanoate (1.5 g). LC-MS: m/z 216.3 (M+H)⁺.

Step B: Compound 302:5-methyl-6-morpholino-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of methyl ethyl 2-morpholino-3-oxobutanoate (500 mg, 2.3mmol), 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (565 mg, 2.3 mmol)in AcOH (20 ml) and xylene (20 mL) was heated to 140° C. for 16 h. Thereaction mixture was concentrated to afford5-methyl-6-morpholino-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.97 (br. s., 2H), 7.43 (d, J=6.7 Hz, 2H), 3.87 (br.s., 2H), 3.81 (br. s., 2H), 3.74 (br. s., 2H), 3.00 (br. s., 4H), 2.54(s, 5H), 1.68 (br. s., 4H), 1.54 (br. s., 2H). LC-MS: m/z 394.3 (M+H)⁺.

Compound 303

Step A:6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 200 mg, 0.39 mmol) and2-methoxypyridin-4-ylboronic acid (178 mg, 1.16 mmol), PdCl₂(dppf) (28mg, 0.04 mmol) and Na₂CO₃ (82 mg, 0.78 mmol) in 1,4-dioxane/water (10mL/1 mL) was stirred and heated to 85° C. for 16 h under N₂ atmosphere.The reaction was then cooled to RT and filtered. The dark filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography, eluting with PE/EA (4/1), to get desired product (40 mg,18% yield) as a white solid. LC-MS: m/z 546.3 (M+H)⁺.

Step B:5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 1 mL, 0.5 mmol) was stirredat RT for 1 h. The mixture was then concentrated to dryness. The residuewas dissolved into con. hydrochloric acid (10 mL) and stirred at 100° C.for 72 h. The reaction mixture was concentrated to afford the desiredproduct.

¹H NMR (DMSO-d₆) δ: 11.20 (br. s., 1H), 8.30 (d, J=7.2 Hz, 2H),7.41-7.37 (m, 2H), 7.30-7.22 (m, 2H), 6.21 (t, J=2.0 Hz, 2H), 3.19 (br.s., 4H), 2.33 (s, 3H), 1.62-1.50 (m, 6H). LC-MS: m/z 402.2 (M+H)⁺.

Compound 304

Step A:5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of ethyl 3-oxobutanoate (18.7 g, 0.143 mol) and3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (synthesized in scheme ofCompound 305, 17.5 g, 0.072 mol) in AcOH (100 mL) was stirred at 95° C.for 4 h. After cooling to room temperature, the solids were collected byfiltration, washed with ethyl acetate, and dried under vacuum to give5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(15 g, 68% yield) as a white solid. LC-MS: m/z 309.1 (M+H)⁺.

Step B:5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

To a solution of5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(synthesized in scheme of Compound 305, 6.5 g, 21.1 mmol) in dry DMF (50mL) was added NaH (60% dispersion in mineral oil, 1.7 g, 42.5 mmol) inportion at 0° C. After addition, the mixture was stirred at 0° C. for 1h. Then the SEM-Cl (5.3 g, 31.7 mmol) was added, and the mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas poured into water (200 mL) and extract with EtOAc (3*200 mL). Thecombined organic layers were washed with water (2*300 mL) and brine (300mL), and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (ethyl acetate:PE=2:1) to get thetitle compound (3.8 g, 41% yield) as a white solid. LC-MS: m/z 439.1(M+H)⁺.

Step C: 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

To a solution of5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(3.4 g, 7.76 mmol) in DCM (30 mL) were added NBS (1.3 g, 7.76 mmol) andEt₃N (0.82 g, 7.76 mmol). The resulting mixture was stirred at ambienttemperature for 3 hours. Then the mixture was washed with water (30 mL),and the aqueous layer was extracted with DCM (30 mL). The combinedorganic layers were washed with brine (30 mL), dried over anhydroussodium sulfate, and concentrated invacuo. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:PE=2:1) to get thetitle compound (3.1 g, 78% yield) as a white solid. LC-MS: m/z 517.2(M+H)⁺.

Step D:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

A mixture of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(100 mg, 0.19 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (59 mg, 0.288mmol), Pd(dppf)Cl₂ (21 mg, 0.029 mmol) and Na₂CO₃ (41 mg, 0.386 mmol) in1.4-dioxane (5 mL) and H₂O (0.5 mL) was stirred at 100° C. for 2 h underN₂. The reaction mixture was then cooled to r.t. and filtered. Thefiltrate was concentrated in vacuo and purified by prep TLC to obtain5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(50 mg) as a white solid. LC-MS: m/z 516.0 (M+H)⁺.

Step E: Compound 304:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(50 mg, 0.097 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture wasstirred at ambient temperature for 2 h. Then the mixture wasconcentrated to dryness. The residue was stirred with saturated sodiumhydrogen carbonate solution to get the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.50 (br. s., 2H), 8.26 (d, J=7.25 Hz, 2H),7.39-7.45 (m, 2H), 7.35-7.38 (m, 2H), 7.28-7.34 (m, 1H), 3.18 (br. s.,4H), 2.22 (s, 3H), 1.61-1.66 (m, 4H), 1.52-1.57 (m, 2H). LC-MS: m/z386.1 (M+H)⁺.

Compound 305

Step A: 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile

To a mixture of 2-(piperidin-1-yl)acetonitrile (7.8 g, 62 mmol) andmethyl benzoate (9.4 g, 68 mmol) in THF (200 mL) was added NaHMDS (2M inTHF, 46 mL, 1.2 eq.) at 0° C. The mixture was stirred at r.t. overnight.The reaction mixture was diluted with EA (300 mL) and quenched withsaturated NH₄Cl. The organic phase was separated, washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography to afford the desired3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile as a white solid. LC-MS:m/z 229.1 (M+H)⁺.

Step B: 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine

The mixture of 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile (5 g,21.902 mmol) and hydrazine (3.3 g, 65.706 mmol) in EtOH/AcOH (5/1, 30mL/6 mL) was refluxed for 16 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (50 mL) and neutralized with10% NaHCO₃. The organic phase was separated, and the the water phase wasextracted with EA (50 mL*2). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel (PE/EA=1/3)to afford 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (2.2 g) as awhite solid.

¹H NMR (DMSO-d₆) δ: 11.52 (br. s., 1H), 7.82 (br. s., 2H), 7.36 (t,J=7.2 Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 4.28 (br. s., 2H), 2.88 (t, J=5.0Hz, 3H), 1.55 (br. s., 3H), 1.46 (d, J=4.0 Hz, 2H). LC-MS: m/z 243.2(M+H)⁺.

Step C:5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (8.43 g,34.8 mmol) and methyl 3-oxobutanoate (9 g, 69.2 mmol) in acetic acid (5mL) was heated to reflux for 2 h. The mixture was cooled to roomtemperature. The suspension was filtered off. The resulting solid waswashed with water and cold methanol to afford5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(7.9 g, 74% yield) as a white solid. LC-MS: m/z 309.2 (M+H)⁺.

Step D:5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(5.5 g, 17.9 mmol) in N,N-dimethylformamide (50 mL) was added sodiumhydride (1.4 g, 35.8 mmol) slowly at 0° C. After addition, the mixturewas stirred at 0° C. for 1 h. (2-(Chloromethoxy)ethyl)trimethylsilane(3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at roomtemperature overnight. The mixture was quenched with brine and extractedwith ethyl acetate (50 mL) three times. The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo to dryness. The residue was purified by column chromatography(methanol:dichloromethane=1:20) to afford5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(2.5 g, 35% yield) as a white solid. LC-MS: m/z 439.2 (M+H)⁺.

Step E:6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)-methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(1.2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) indichloromethane (20 mL) at room temperature was added N-bromosuccinimide(0.58 g, 3.47 mmol) at room temperature. Then the mixture was stirred atroom temperature for 2 h. The mixture was concentrated. The residue waspurified by column chromatography (methanol:dichloromethane=1:20) toafford6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(1.3 g, 80% yield) as a white solid. LC-MS: m/z 519.2, 517.2 (M+H)⁺.

Step F:4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzamide

To a solution of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.194 mmol) and (4-carbamoylphenyl)boronic acid (48.3 mg, 0.293mmol) in dioxane/H₂O (5 mL/1 mL) was added1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogenatmosphere overnight. The reaction mixture was filtered and concentratedin vacuo. The residue was purified by column chromatography(methanol:dichloromethane=1/20) to afford4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzamide(60 mg, 55% yield) as a white solid. LC-MS: m/z 558.3 (M+H)⁺.

Step G: Compound 305:4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzamide

A mixture of4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzamide(60 mg, 0.11 mmol) in CF₃COOH (2 mL) was heated to 60° C. for 3 h. Themixture was cooled to room temperature and concentrated in vacuo toremove solvent. The resulting residue was washed with saturated aqueoussodium bicarbonate to afford6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.96-8.06 (m, J=8.06 Hz, 2H), 7.68 (br. s., 2H),7.59 (br. s., 3H), 7.46-7.54 (m, J=7.79 Hz, 2H), 3.55 (br. s., 4H), 2.42(s, 3H), 1.94-2.10 (m, 4H), 1.59 (br. s., 2H). LC-MS: m/z 428.3 (M+H)⁺.

Compound 306

Step A: 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 100 mg, 0.194 mmol) and(4-(methylsulfonyl)phenyl)boronic acid (78 mg, 0.386 mmol) indioxane/H₂O (5 mL/1 mL) was added1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogenatmosphere overnight. The reaction mixture was filtered and concentratedin vacuo. The residue was purified by column chromatography(methanol:dichloromethane=1/20) to afford5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(60 mg, 52.6% yield) as a white solid. LC-MS: m/z 593.3 (M+H)⁺.

Step B: Compound 306:5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(60 mg, 0.1 mmol) in CF₃COOH (2 mL) was heated to 60° C. for 3 h. Themixture was cooled to room temperature and concentrated in vacuo toremove solvent. The resulting residue was washed with saturated aqueoussodium bicarbonate to afford5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 8.05 (d, J=7.52 Hz, 2H), 7.44-7.69 (m, 7H), 3.70(br. s., 2H), 3.33 (d, J=8.33 Hz, 2H), 3.13 (s, 3H), 2.58 (d, J=12.09Hz, 2H), 2.44 (s, 3H), 1.73-1.97 (m, 3H). LC-MS: m/z 463.2 (M+H)⁺.

Compound 307

Step A:6-(4-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 100 mg, 0.19 mmol),4-aminophenylboronic acid hydrochloric salt (60 mg, 0.58 mmol),PdCl₂(dppf) (8.4 mg, 0.02 mmol) and Na₂CO₃ (55 mg, 0.78 mmol) in1.4-dioxane/water (10 mL/1 mL) was stirred and heated to 85° C. for 16 hunder N₂ atmosphere. The reaction was then cooled to RT and filtered.The dark filtrate was concentrated in vacuo. The residue was purified byflash column chromatography, eluting with PE/EA (4/1), to give desiredproduct (30 mg, 29% yield) as a white solid. LC-MS: m/z 530.3 (M+H)⁺.

Step B:6-(4-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of tert-butyl4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate(40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 mL, 5 mmol) was stirredat RT for 1 h. The mixture was concentrated to afford the desiredproduct.

¹H NMR (DMSO-d₆) δ: 11.27 (br. s., 1H), 8.12 (d, J=7.2 Hz, 2H), 7.47 (t,J=7.2 Hz, 2H), 7.40 (d, J=7.2 Hz, 1H), 6.93 (t, J=8.4 Hz, 2H), 6.60 (d,J=8.4 Hz, 2H), 5.12 (s, 2H), 3.08 (d, J=4.2 Hz, 4H), 2.26 (s, 3H),1.62-1.50 (m, 6H). LC-MS: m/z 400.2 (M+H)⁺.

Compound 308

Step A:N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[dihyd1,5-a]pyrimidin-6-yl)phenyl)acetamide

A suspension of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 100 mg, 0.19 mmol) and4-acetamidophenylboronic acid (100 mg, 0.58 mmol), PdCl₂(dppf) (8.4 mg,0.02 mmol) and Na₂CO₃ (55 mg, 0.78 mmol) in 1.4-dioxane/water (10 mL/1mL) was stirred and heated to 85° C. for 16 h under N₂ atmosphere. Thereaction was then cooled to RT and filtered. The dark filtrate wasconcentrated in vacuo The residue was purified by flash columnchromatography, eluting with PE/EA (4/1), to give desired product (20mg, 18% yield) as a white solid. LC-MS: m/z 572.3 (M+H)⁺.

Step B:N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide

The mixture ofN-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide(20 mg, 0.03 mmol) and HCl in MeOH (0.5 mol, 10 mL, 5 mmol) was stirredat RT for 1 h to afford the desired product.

¹H NMR (DMSO-d₆) δ: 11.35 (br. s., 1H), 10.02 (br. s., 1H), 8.12 (d,J=7.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 7.40 (t,J=7.2 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 3.08 (d, J=4.8 Hz, 4H), 2.26 (s,3H), 2.07 (s, 3H), 1.67-1.50 (m, 6H). LC-MS: m/z 442.3 (M+H)⁺.

Compound 309

Step A:6-(6-hydroxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 358, 40 mg, 0.10 mmol) in con. hydrochloric acid (10 mL) wasstirred at 100° C. for 48 h to afford the desired product.

¹H NMR (DMSO-d₆) δ: 8.29 (d, J=7.2 Hz, 2H), 7.39 (t, J=8.0 Hz, 3H), 7.26(d, J=7.2 Hz, 1H), 7.14 (s, 1H), 6.30 (d, J=9.6 Hz, 1H), 3.19 (br. s.,4H), 2.12 (s, 3H), 1.62-1.50 (m, 6H). LC-MS: m/z 402.3 (M+H)⁺.

Compound 310

Step A: ethyl 3-oxo-2-(thiazol-4-yl)butanoate

To a solution of ethyl 2-(thiazol-4-yl)acetate (500 mg, 2.92 mmol) inTHF (10 mL) was added LDA (1.5 M in THF, 2.3 mL, 3.5 mmol) dropwise at−30˜−35° C. The mixture was stirred at −30˜−35° C. for 30 min, andacetic anhydride (360 mg, 3.5 mmol) was added dropwise. Then the mixturewas warmed to room temperature and stirred for 6 h. The mixture waspoured into saturated NH₄Cl and extracted with EA (3*10 mL). Thecombined organic phase was washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography to afford the desired ethyl3-oxo-2-(thiazol-4-yl)butanoate as a brown oil (500 mg, 80% yield).

Step B: Compound 310:5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3-oxo-2-(thiazol-4-yl)butanoate (200 mg, 0.94 mmol) and3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (227 mg, 0.94 mmol) inAcOH (5 mL) was stirred at 95° C. for 2 h to give title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.52 (br. s., 1H), 9.17 (d, J=1.88 Hz,1H), 8.13 (d, J=6.98 Hz, 2H), 7.82 (d, J=1.88 Hz, 1H), 7.45-7.51 (m,2H), 7.37-7.44 (m, 1H), 3.08-3.11 (m, 4H), 2.42 (s, 3H), 1.67 (br. s.,4H), 1.56-1.61 (m, 2H). LC-MS: m/z 392.3 (M+H)⁺.

Compound 311

Step A: ethyl 2-(4-hydroxypiperidin-1-yl)-3-oxobutanoate

To a solution of piperidin-4-ol (200 mg, 2.0 mmol) and TEA (0.3 mL, 2.4mmoL) in EtOH (10 mL) was added ethyl 2-chloro-3-oxobutanoate (442 mg,2.4 mmol) dropwise at 0° C. The mixture was stirred at 40° C. for 18 h.The mixture was concentrated and purified by flash columnchromatography, eluting with PE/EA (4/1), to get the desired product asa yellow solid (120 mg, 26% yield). LC-MS: m/z 230.2 (M+H)⁺.

Step B:6-(4-hydroxypiperidin-1-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (116 mg, 0.66 mmol) andethyl 2-(4-hydroxypiperidin-1-yl)-3-oxobutanoate (120 mg, 0.66 mmol) inAcOH (5 mL) was stirred at 100° C. for 1 h. After removal of AcOH, 10%of NaHCO₃ was added to afford the desired product.

¹H NMR (DMSO-d₆) δ: 11.16 (br. s., 1H), 8.08 (d, J=7.2 Hz, 2H), 7.46 (t,J=7.2 Hz, 2H), 7.39 (t, J=7.2 Hz, 1H), 3.42-3.17 (m, 3H), 3.03 (br. s.,4H), 2.68 (br. s., 2H), 2.51 (s, 3H), 1.82-1.79 (m, 2H), 1.64-1.56 (m,6H), 1.21 (br. s., 2H). LC-MS: m/z 408.6 (M+H)⁺.

Compound 312

Step A: methyl 2-(4-methoxyphenyl)-3-oxopentanoate

To a solution of methyl 2-(4-methoxyphenyl)-3-oxopentanoate (2.0 g,11.10 mmol.) in THF (20 mL) was added LDA (2.0 M in THF, 6.6 mL, 13.32mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 30 min,and propionyl chloride (1.1 mL, 13.32 mmol) was added dropwise. Then themixture was slowly warmed to RT and stirred for 10 min. The mixture waspoured slowly to saturated aq. NH₄Cl and extracted with EA (30 mL*3).The combined organic phase was washed with brine, dried over anhydrousMgSO₄, and concentrated in vacuo to get the desired product as a yellowoil (4.0 g, crude) which was directly used to the next step withoutfurther purification. LC-MS: m/z 237.2 (M+H)⁺.

Step B:5-ethyl-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (1.3 g, 4.25 mmol) andmethyl 2-(4-methoxyphenyl)-3-oxopentanoate (1.3 eq.) in AcOH (10 mL) wasstirred at 100° C. for 1 h. After removal of AcOH, 10% of NaHCO₃ wasadded to afford the desired product.

¹H NMR (DMSO-d₆) δ: 11.84 (br. s., 1H), 7.46-7.33 (m, 10H), 7.22 (d,J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 3.81 (s, 3H), 2.43 (dd, J=7.2 Hz,7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H). LC-MS: m/z 422.7 (M+H)⁺.

Compound 313

Step A:2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetonitrile

The solution of5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 340, 230 mg, 0.52 mmol), TMSCN (77.4mg, 0.78 mmol) and Cs₂CO₃ (338.8 mg, 1.04 mmol) in acetonitrile (30 mL)was stirred at reflux for 8 h. The reaction was then cooled to RT andfiltered. The dark filtrate was concentrated in vacuo to afford thedesired product as a brown solid.

¹H NMR (DMSO-d₆) δ: 7.55 (m, 4H), 7.37 (dd, J=6.0 Hz, 7.2 Hz, 3H),7.27-7.20 (m, 4H), 7.11 (d, J=7.2 Hz, 1H), 6.97 (dd, J=2.0 Hz, 2.0 Hz,2H), 3.80 (s, 3H), 3.62 (s, 2H). LC-MS: m/z 433.8 (M+H)⁺.

Compound 314

Step A:6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehyde

A mixture of5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(900 mg, 2.12 mmol) and PCC (synthesized in scheme of Compound 338, 688mg, 3.18 mmol) in DCM (100 mL) was stirred at RT overnight. The mixturewas filtered, washed with DCM, and concentrated in vacuo to get thedesired product as a yellow solid (900 mg, 100%). LC-MS: m/z 422.2(M+H)⁺.

Step B:(E)-6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehydeoxime

The solution of6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehyde(1.0 g, 2.37 mmol), hydroxylamine hydrochloride (1.8 g, 26.1 mmol) andsodium hydroxide (104 mg, 2.61 mmol) in EtOH/H₂O (90 ml/10 mL) wasstirred at RT overnight. The reaction mixture was concentrated in vacuoand purified by flash column chromatography, eluting with DCM/MeOH(30/1), to get the desired product as a yellow solid (330 mg, 32%yield). LC-MS: m/z 437.2 (M+H)⁺.

Step C:6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbonitrile

The solution of(E)-6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehydeoxime (150 mg, 0.34 mmol) in DCM (10 mL) was added thionyl chloride (0.2mL, 3.44 mmol) dropwise at RT for 3 h. The reaction mixture was dilutedwith DCM, washed with saturated NaHCO₃ and extracted with DCM (30 mL*3).The combined organic phase was washed with brine, dried over anhydrousMgSO₄ and concentrated to afford the desired product.

¹H NMR (DMSO-d₆) δ: 7.51-7.01 (m, 12H), 7.7.01-6.99 (m, 2H), 3.81 (s,3H), 3.18 (s, 1H). LC-MS: m/z 418.9 (M+H)⁺.

Compound 315

Step A:6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxamide

A solution of6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbonitrile(Compound 314, 40 mg, 0.10 mmol) in MeOH (10 ml) were added hydrogenperoxide (30%, 32.5 mg, 0.96 mmol) and sodium hydroxide (1N, 38.4 mg,0.96 mmol). The resultant mixture was stirred at 40° C. for 1 h. Thesaturated sodium sulfite was added to afford the desired product.

¹H NMR (DMSO-d₆) δ: 7.55-7.46 (m, 4H), 7.34-7.02 (m, 8H), 6.86-0.83 (m,2H), 3.77 (s, 3H). LC-MS: m/z 436.9 (M+H)⁺.

Compound 316

Step A:3-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (184 mg, 0.76mmol) and 4-(3,3-difluoropyrrolidin-1-yl)-3-phenyl-1H-pyrazol-5-amine(200 mg, 0.76 mmol, synthesized in the scheme of Compound 272) in AcOH(50 mL) was stirred at 100° C. for 1 h to afford the title compound 2.

¹H NMR (DMSO-d₆) δ: 11.99 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H),8.29-8.44 (m, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (dd, J=8.2, 1.2 Hz, 2H),7.94 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.6, 2.0 Hz, 1H), 7.57 (dd, J=8.2,4.2 Hz, 1H), 7.40-7.52 (m, 3H), 3.62 (t, J=12.8 Hz, 2H), 3.45 (t, J=7.0Hz, 2H), 2.42-2.59 (m, 2H), 2.32 (s, 3H). LC-MS: m/z 458.0 (M+H)⁺.

Compound 317

Step A: methyl 2-(6-nitropyridin-3-yl)-3-oxobutanoate

To a solution of 5-chloro-2-nitropyridine (3.2 g, 20 mmol) in DMSO (20mL) were added methyl 3-oxobutanoate (3.5 g, 30 mmol) and K₂CO₃ (5.5 g,40 mmol). The mixture was stirred at 110° C. for 8 h. The mixture wascooled to r.t. and poured into H₂O (60 mL) and extracted with EA (3*50mL). The extract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyto afford the title compound 2 as a yellow solid (470 mg, 10% yield).LC-MS: m/z 239.0 (M+H)⁺.

Step B:3-(3,3-difluoropyrrolidin-1-yl)-5-methyl-6-(6-nitropyridin-3-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of intermediate 2 (470 mg, 2.0 mmol) and4-(3,3-difluoropyrrolidin-1-yl)-3-phenyl-1H-pyrazol-5-amine (521 mg, 2.0mmol, synthesized in the scheme of Compound 272) in AcOH (8 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t.,concentrated, and neutralized with saturated NaHCO₃ solution until pH=7.The precipitate was filtered off and washed with EA (3*2 mL) to affordthe title compound 3 as a yellow solid (400 mg, 45% yield).

¹H NMR (DMSO-d₆) δ: 12.17 (s, 1H), 8.63-8.73 (m, 1H), 8.41 (d, J=8.2 Hz,1H), 8.25 (dd, J=8.2, 2.0 Hz, 1H), 7.98 (d, J=6.6 Hz, 2H), 7.38-7.55 (m,3H), 3.61 (t, J=12.8 Hz, 2H), 3.44 (t, J=6.8 Hz, 2H), 2.44-2.58 (m, 2H),2.37 (s, 3H). LC-MS: m/z 452.9 (M+H)⁺.

Step C:6-(6-aminopyridin-3-yl)-3-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of intermediate 3 (390 mg, 0.09 mmol) in MeOH (8 mL) wasadded Pd/C (10 mg). The mixture was stirred at r.t. under H₂ atmosphereovernight. The mixture was filtered through celite, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(DCM/MeOH 20:1) to afford the title compound 4 as a yellow solid (270mg, 74% yield). LC-MS: m/z 422.9 (M+H)⁺.

Step D:3-(3,3-difluoropyrrolidin-1-yl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of intermediate 4 (270 mg, 0.6 mmol) in EtOH (5 mL) wasadded 2-chloroacetaldehyde (40% in water, 0.3 mL) and NaHCO₃(161 mg, 1.9mmol). The mixture was refluxed for 2 h. The mixture was cooled to r.t.and evaporated. The residue was dissolved in DCM (10 mL), washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to affordthe title compound 5.

¹H NMR (DMSO-d₆) δ: 12.38 (br. s., 1H), 8.94 (s, 1H), 8.38 (d, J=1.8 Hz,1H), 8.23 (d, J=1.8 Hz, 1H), 8.04 (d, J=9.4 Hz, 1H), 7.96-8.01 (m, 2H),7.90-7.95 (m, 1H), 7.44-7.52 (m, 3H), 3.64 (t, J=12.8 Hz, 2H), 3.47 (t,J=7.0 Hz, 2H), 2.47-2.60 (m, 2H), 2.40 (s, 3H). LC-MS: m/z 446.9 (M+H)⁺.

Compound 318

Step A:5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of methyl 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.8mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.85 mmol) inAcOH (2 ml) was refluxed for 30 min under N₂ protection. The mixture wascooled to the RT, concentrated, and neutralized with saturated sodiumhydrogen carbonate solution to adjust to pH=7. The precipitates werecollected by filtration, washed with petroleum ether, and dried toobtain the desired product as a yellow solid (50 mg, 62% yield). LC-MS:m/z 429.2 (M+H)⁺

Step B:4,5-dimethyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(34 mg, 0.08 mmol) and Cs₂CO₃ (26 mg, 0.08 mmol) in DMF (2 ml) atambient temperature was added MeI (22 mg, 0.16 mmol) dropwise. Themixture was stirred for 4 h at ambient temperature. The mixture wascooled to the RT, washed with saturated sodium hydrogen carbonatesolution, and extracted with DCM (3*30 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo to obtain the desired product.

¹H NMR (DMSO-d₆) δ: 8.95 (dd, J=1.6 Hz, 1.6 Hz, 1H), 8.42 (d, J=7.6 Hz,1H), 8.11 (d, J=8.8 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0 Hz,2.0 Hz, 1H), 7.59 (dd, J=4.4 Hz, 4.0 Hz, 1H), 7.47 (s, 5H), 7.39-7.37(m, 2H), 7.32-7.28 (m, 3H), 3.37 (s, 3H), 2.27 (s, 3H). LC-MS: m/z 443.3(M+H)⁺.

Compound 319

Step A: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate

To a solution of methyl 2-(quinolin-6-yl)acetate (10 g, 49.7 mmol) inTHF (300 mL) was added dropwise LDA (1.5 M in THF, 39.8 mL, 59.7 mmol)at −30˜−35° C. The mixture was stirred at −30˜−35° C. for 30 min and2-(benzyloxy)acetyl chloride (9.15 g, 49.7 mol) was added dropwise. Thenthe mixture was stirred at r.t. for 6 h. The mixture was poured slowlyto saturated NH₄Cl and extracted with EA (50 mL×3). The combined organicphase was washed with brine, dried over anhydrous MgSO₄ and concentratedin vacuo. The residue was purified by flash chromatography to afford thedesired methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate as a brownoil (13.6 g, 80% yield). LC-MS: m/z 350.2 (M+H)⁺.

Step B:5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6g, 0.024 mol) and 3,4-diphenyl-1H-pyrazol-5-amine (5.64 g, 0.024 mol)was dissolved in AcOH (300 ml). The mixture was warmed up to 95° C. for4 h. After cooling to room temperature, the precipitate was filtered,wash with EtOAc, and dried under vacuum to get5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(10 g, 78% yield) as a yellow solid. LC-MS: m/z 535.2 (M+H)⁺.

Step C: Compound 319:5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(10 g, 18.7 mmol) in DCM (100 ml) was added BCl₃ (25 ml, 25 mmol, 1.0Min DCM) at 0° C. The resultant mixture was stirred at 0° C. for 4 hours.The reaction was quenched with MeOH and concentrated. The residue wasstirred with sodium hydrogen carbonate solution and ethyl acetate for 30min to afford5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.65 (br. s., 1H), 8.96 (d, J=2.69 Hz, 1H), 8.40(d, J=7.79 Hz, 1H), 8.08 (d, J=8.60 Hz, 1H), 8.01 (s, 1H), 7.79 (d,J=8.87 Hz, 1H), 7.59 (dd, J=4.03, 8.06 Hz, 1H), 7.36-7.51 (m, 9H), 5.64(br. s., 1H), 4.36 (br. s., 2H). LC-MS: m/z 445.8 (M+H)⁺.

Compound 320

Step A:5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a suspension of5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 319, 500 mg, 1.126 mmol) in DCM (3 ml) was added dropwiseSOCl₂ (670 mg, 5.631 mmol) at 0° C. The resultant mixture was thenstirred at room temperature overnight. The suspension was filtered,washed with ethyl acetate, and dried under vacuum. The residue waspurified by prep-TLC (DCM:MeOH=20:1) to get5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(300 mg). LC-MS: m/z 463.1 (M+H)⁺.

Step B: Compound 320:5-((1H-pyrazol-1-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.22 mmol) in DMF (10 mL) were added 1H-pyrazole (30 mg, 0.433mmol), K₂CO₃ (60 mg, 0.433 mmol) and KI (5 mg, 0.03 mmol). The mixturewas stirred at 80° C. for 2 h to afford5-((1H-pyrazol-1-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 12.45 (br. s., 1H), 8.93 (d, J=2.96 Hz, 1H), 8.27(d, J=8.06 Hz, 1H), 8.00 (d, J=8.33 Hz, 1H), 7.75 (br. s., 1H), 7.64(br. s., 1H), 7.56 (dd, J=4.03, 8.33 Hz, 1H), 7.26-7.52 (m, 10H), 6.15(s, 1H), 5.22 (br. s., 2H). LC-MS: m/z 494.8 (M+H)⁺.

Compound 321

Step A:2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetonitrile

To a solution of5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 320, 1 g, 22 mmol) in CH₃CN (10 mL)were added K₂CO₃ (600 mg, 4.33 mmol) and NaCN (100 mg, 22 mmol). Themixture was stirred at r.t. for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and concentrated in vacuo to dryness.The residue was purified by silica gel chromatography(methanol:dichloromethane=1:10) to afford2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetonitrile(600 mg, 61% yield). LC-MS: m/z 454.2 (M+H)⁺.

Step B: Compound 321:5-((1H-1,2,4-triazol-5-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetonitrile(170 mg, 0.375 mmol) in butan-1-ol (10 mL) were added K₂CO₃ (60 mg,0.433 mmol) and formohydrazide (225 mg, 3.75 mmol). The mixture wasstirred at 160° C. under microwave irradiation for 2 h to afford5-((1H-1,2,4-triazol-5-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 9.20 (br. s., 1H), 9.03 (d, J=7.79 Hz, 1H), 8.32(br. s., 1H), 8.24 (br. s., 2H), 7.95-8.10 (m, 2H), 7.56 (br. s., 3H),7.25-7.51 (m, 9H), 4.17 (br. s., 2H). LC-MS: m/z 495.8 (M+H)⁺.

Compound 322

Step E: Compound 322:3-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dione

To a mixture of hydantoin (324 mg, 3.24 mmol) in DMF (6 mL) was addedNaH (60% dispersion in mineral oil, 143 mg, 3.56 mmol) in portions at 0°C. After addition, the mixture was stirred at 0° C. for 30 min. Then the5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(150 mg, 0.324 mmol, synthesized in scheme of Compound 278) was addedinto the mixture. The reaction mixture was warmed to 80° C. and stirredovernight. The reaction was quenched with brine and mixed with EA toafford the title compound.

¹H NMR (400 MHz, TFA) δ: 9.37 (d, J=8.06 Hz, 1H), 9.29 (d, J=5.37 Hz,1H), 8.61 (br. s., 2H), 8.20-8.42 (m, 2H), 7.47-7.66 (m, 7H), 7.13-7.35(m, 3H), 5.00 (br. s., 1H), 4.35 (br. s., 1H), 3.22 (br. s., 2H). LC-MS:m/z 527.0 (M+H)⁺.

Compound 323

Step A: 3-(4-methoxybenzyl)imidazolidine-2,4-dione

To a solution of imidazolidine-2,4-dione (500 mg, 5 mmol) in DMF (10 mL)was added NaH (60% dispersion in mineral oil, 240 mg, 6 mmol) inportions at 0° C. After addition, the mixture was stirred at 0° C. for40 min. Then PMBBr (1.0 g, 5 mmol) was added dropwise. The resultantmixture was warmed to 80° C. and stirred overnight. The reaction wasquenched with brine (30 mL). The suspension was filtered off. The filtercake was washed with brine and EA, and then dried in vacuo to get thetitle compound (430 mg) as a white solid. LC-MS: m/z 221.1 (M+H)⁺.

Step B:3-(4-methoxybenzyl)-1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dione

To a mixture of hydantoin (124 mg, 0.562 mmol) in DMF (6 mL) was addedNaH (60% dispersion in mineral oil, 27 mg, 0.674 mmol) in portions at 0°C. After addition, the mixture was stirred at 0° C. for 30 min. Then the5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg, 0.281 mmol, Synthesized in scheme of Compound 278) was addedinto the mixture. The reaction mixture was warmed to 80° C. and stirredovernight. The reaction was quenched with brine and then mixed with EA.The mixture was filtered off. The filter cake was purified by prep HPLCto get the title compound (100 mg) as a yellow solid. LC-MS: m/z 647.0(M+H)⁺.

Step C: Compound 323:1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dione

A mixture of3-(4-methoxybenzyl)-1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dioneand CF₃SO₃H (0.5 mL) in TFA (2 mL) was heated to reflux overnight. Thereaction mixture was cooled to room temperature, quenched with aq.NaHCO₃ to pH=7-8 to afford the title compound.

¹H NMR (400 MHz, TFA) δ: 9.34 (d, J=8.33 Hz, 1H), 9.25 (d, J=5.10 Hz,1H), 8.49-8.64 (m, 2H), 8.34 (d, J=8.06 Hz, 1H), 8.24 (dd, J=8.06, 5.64Hz, 1H), 7.55-7.71 (m, 6H), 7.46-7.53 (m, 2H), 7.43 (d, J=6.72 Hz, 2H),4.88 (br. s., 2H), 4.27 (br. s., 2H). LC-MS: m/z 527.0 (M+H)⁺.

Compound 324

Step A: Compound 324:5-((2-oxoimidazolidin-1-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(100 mg, 0.216 mmol, Synthesized in scheme of Compound 278),imidazolidin-2-one (93 mg, 1.08 mmol) and K₂CO₃ (136 mg, 0.259 mmol) inDMF (3 mL) was heated to 80° C. and stirred overnight. The reactionmixture was quenched with brine and then mixed with EA to get the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.88 (br. s., 1H), 8.36 (d, J=7.52 Hz, 1H),8.00 (d, J=8.06 Hz, 1H), 7.89 (br. s., 1H), 7.78 (d, J=8.33 Hz, 1H),6.95-7.68 (m, 11H), 6.19 (br. s., 1H), 4.09-4.33 (m, 2H), 3.58 (br. s.,2H), 3.21 (br. s., 2H). LC-MS: m/z 513.0 (M+H)⁺.

Compound 325

Step A:3-(3-hydroxycyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid (Synthesized in scheme of Compound 329, 100 mg, 0.2 mmol) in DMF (5mL) were added methanamine hydrochloride (16 mg, 0.2 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (91 mg, 0.2 mmol) and N,N-diisopropylethylamine (65mg, 0.5 mmol). The mixture was stirred at r.t. for 30 min. The mixturewas diluted with H₂O (15 mL) and extracted with DCM (3*15 mL). Theextracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound 2.

¹H NMR (DMSO-d₆) δ: 13.00 (br. s., 1H), 8.92-9.12 (m, 1H), 8.65 (d,J=4.6 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.07-8.15 (m, 1H), 8.05 (br. s.,1H), 7.86 (d, J=7.4 Hz, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.40-7.52 (m, 5H),7.28-7.39 (m, 5H), 2.44 (d, J=4.6 Hz, 3H). LC-MS: m/z 472.2 (M+H)⁺.

Compound 326

Step C:6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline

The solution of2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(18 g, 42 mmol, Compound 275), DMAP (1 g) and PCl₅ (80 mg) in POCl₃ (180mL) was stirred at 100° C. overnight. After cooling to room temperature,the solvent was removed by vacuum. The residue was cooled to 0° C. MeOH(60 mL) was added to quench the reaction. The resultant mixture wasdiluted with DCM (450 ml), washed with saturated NaHCO₃ (150 ml) andbrine (100 ml), dried over anhydrous sodium sulfate, and concentrated toget crude product of6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline (13g) which was used in the next step without further purification. LC-MS:m/z 467.1 (M+H)⁺.

Step D:6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline

To a solution of6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(13.0 g, crude, 27.8 mmol) in DCM/MeOH (200 mL, 1:1) cooled at 0° C. wasadded sodium methoxide (14.9 mL, 5.0 M in methanol) dropwise. Then themixture was stirred at 0° C. for 1 hour. Saturated NH₄Cl (150 mL) wasadded to quench the reaction. The resultant mixture was extracted withDCM (500 mL), washed with brine (150 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by flashcolumn (DCM/MeOH=40:1) to obtain6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(9.0 g) as a pale yellow solid.

¹H NMR (DMSO-d₆): δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.45-8.52 (m, 1H),8.13-8.21 (m, 2H), 7.88 (dd, J=8.6, 1.9 Hz, 1H), 7.59-7.68 (m, 3H),7.42-7.48 (m, 7H), 7.34-7.41 (m, 1H), 4.25 (s, 3H). LC-MS: m/z 463.1(M+H)⁺.

Step E:N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide

A mixture of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(100 mg, 0.216 mmol), cyclopropanecarboxamide (55.2 mg, 0.65 mmol),palladium(II) acetate (9.7 mg, 0.04 mmol), xantphos (37.5 mg, 0.06 mmol)and sodium carbonate (140.8 mg, 0.43 mmol) in 1,4-dioxane (10 mL) wasstirred at 100° C. under N₂ for 12 h to afford the desired product.

¹H NMR (DMSO-d₆) δ: 9.41-9.31 (m, 2H), 8.73-8.72 (m, 1H), 8.47-8.32 (m,1H), 7.80-7.38 (m, 14H), 1.15-1.32 (m, 5H). LC-MS: m/z 498.2 (M+H)⁺.

Compound 327

Step A:N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)propionamide

A mixture of6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoline(Synthesized in scheme of Compound 326, 100 mg, 0.216 mmol),propionamide (47.4 mg, 0.65 mmol), palladium(II) acetate (9.7 mg, 0.04mmol), xantphos (37.5 mg, 0.06 mmol) and sodium carbonate (140.8 mg,0.43 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under N₂ for 12h to afford the desired product.

¹H NMR (DMSO-d₆) δ: 12.92 (br. s., 1H), 10.08 (s, 1H), 8.94 (d, J=2.8Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H),7.75 (dd, J=1.6 Hz, 1.6 Hz, 1H), 7.55 (dd, J=4.4 Hz, 4.0 Hz, 4H),7.51-7.41 (m, 4H), 7.39-7.35 (m, 6H), 2.28 (dd, J=7.6 Hz, 7.2 Hz, 2H),0.94 (t, J=7.6 Hz, 3H). LC-MS: m/z 486.8 (M+H)⁺.

Compound 328

Step A:N-((1H-pyrazol-3-yl)methyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxamide

To a solution of7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid (Synthesized in scheme of Compound 329, 100 mg, 0.2 mmol) in DMF (5mL) were added (1H-pyrazol-3-yl)methanamine (23 mg, 0.2 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (91 mg, 0.2 mmol) and N,N-diisopropylethylamine (65mg, 0.5 mmol). The mixture was stirred at r.t. for 30 min. The mixturewas diluted with H₂O (15 mL) and extracted with DCM (3*15 mL). Theextracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound 2.

¹H NMR (DMSO-d₆) δ: 12.51 (br. s., 1H), 8.85 (br. s., 1H), 8.54-8.94 (m,1H), 8.18 (d, J=7.2 Hz, 1H), 7.82-7.94 (m, 2H), 7.78 (d, J=9.0 Hz, 1H),7.40-7.66 (m, 6H), 7.11-7.40 (m, 7H), 5.85 (br. s., 1H), 4.22 (br. s.,2H). LC-MS: m/z 538.3 (M+H)⁺.

Compound 329

Step A: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate

To a solution of methyl 2-(quinolin-6-yl)acetate (10.0 g, 49.7 mmol) inTHF (60 mL) was added dropwise LDA (2.0 mol/L in THF, 29.8 mL) and HMPA(1.8 g, 9.9 mmol) at −78° C. After addition, the mixture was stirred at−78° C. for 0.5 h. The mixture was then cooled to −78° C.2-(benzyloxy)acetyl chloride (11.0 g, 59.6 mmol) in dry THF (10 mL) wasadded slowly and stirred at r.t. overnight. The reaction mixture wasdiluted with EA (60 mL), quenched with NH₄Cl solution, extracted with EA(3*60 mL). The combined organic phase was washed with water and brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (EtOAc/PE=1/4) to afford the title compound 2 (8.6 g, 48% yield).LC-MS: m/z 350.1 (M+H)⁺.

Step B:5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6 g,24.6 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (5.8 g, 24.6 mol) in AcOH(100 mL) was stirred at 100° C. for 4 h. After cooling to roomtemperature, the precipitate was filtered, wash with EA (3*10 mL), anddried under vacuum to afford the title compound 3 as a yellow solid(10.0 g, 78% yield). LC-MS: m/z 535.2 (M+H)⁺.

Step C:5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of Intermediate 3 (10.0 g, 18.7 mmol) in DCM (100 mL) wasadded BCl₃(1.0 mol/L in DCM, 25 mL) at 0° C. The resultant mixture wasstirred at 0° C. for 4 h. The reaction was quenched with MeOH andevaporated. The residue was stirred with 10% NaHCO₃(10 mL) aqueoussolution and EA (10 mL) for 30 min. The precipitate was filtered off,washed with EA (3*2 mL) and dried under vacuum to afford the titlecompound 4 (8.0 g, 96% yield). LC-MS: m/z 445.1 (M+H)⁺.

Step D:7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehyde

To a solution of Intermediate 4 (4.4 g, 10 mmol) in 1,2-dichloroethane(50 mL) was added MnO₂ (8.7 g, 100 mmol). The mixture was refluxed for 2days. The reaction was cooled to r.t. and filtered through celite. Thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography to afford the title compound 5 as a brown solid (1.5 g,34% yield). LC-MS: m/z 443.1 (M+H)⁺.

Step E:7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

To a solution of Intermediate 5 (415 mg, 0.9 mmol) and NaH₂PO₄ (702 mg,4.5 mmol) in DMSO/H₂O (5 mL/5 mL) was added sodium chlorite (203 mg in 1mL H₂O, 2.3 mmol) at 0° C. After addition, the mixture was stirred atr.t. for 1 h and poured into H₂O (10 mL). The precipitate was filteredoff, washed with MeOH (3*1 mL) and dried in vacuo to afford the titlecompound 6 as a brown solid (300 mg, 73%). LC-MS: m/z 459.1 (M+H)⁺

Step F:N-(2-hydroxyethyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxamide

To a solution of Intermediate 6 (140 mg, 0.3 mmol) in DMF (5 mL) wereadded 2-aminoethanol (22 mg, 0.4 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (137 mg, 0.4 mmol) and N,N-diisopropylethylamine (97mg, 0.8 mmol). The mixture was stirred at r.t. for 30 min. The mixturewas diluted with H₂O (15 mL) and extracted with DCM (3*15 mL). Theextracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound 7.

¹H NMR (DMSO-d₆) δ: 8.81 (br. s., 1H), 8.24 (d, J=7.8 Hz, 1H), 8.18 (br.s., 1H), 7.75-7.94 (m, 3H), 7.44-7.57 (m, 5H), 7.35 (br. s., 3H), 7.29(t, J=7.4 Hz, 2H), 7.12-7.17 (m, 1H), 3.25-3.30 (m, 2H), 3.10 (d, J=5.6Hz, 2H). LC-MS: m/z 502.2 (M+H)⁺.

Compound 330

Step E: Compound 330:6-(4-aminoquinazolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of Intermediate 5 (170 mg, 0.41 mmol, synthesized in scheme ofCompound 245) and formamide (5 mL) was stirred at 180° C. for 2 h. undermicrowave irradiation. The mixture was concentrated under vacuum toafford the title compound 6.

¹H NMR (DMSO-d₆) δ: 8.40 (s, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.90-7.63 (m,4H), 7.53-7.24 (m, 11H), 2.23 (s, 3H). LC-MS: m/z 445.1 (M+H)⁺.

Compound 331

Step A: methyl 2-(quinoxalin-6-yl)acetate

To 2-(quinoxalin-6-yl)acetic acid (1.0 g, 5.31 mmol) in methanol (20 mL)was added slowly conc. H₂SO₄ (1.0 mL) at 0° C., and the mixture wasrefluxed overnight. The reaction mixture was concentrated in vacuo, andthe residue dissolved in EA. The organic solution was washed withsaturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, and concentratedin vacuo. The residue was purified by flash chromatography, eluting withPE/EA=4/1, to obtain the desired product as a yellow oil (0.47 g, 43%yield). LC-MS: m/z 203.2 (M+H)⁺.

Step B: methyl 3-oxo-2-(quinoxalin-6-yl)butanoate

To a solution of methyl methyl 2-(quinoxalin-6-yl)acetate (0.45 g, 2.23mmol) in THF (20 mL) was added LDA (2.0 M in THF, 1.4 mL, 2.90 mmol)dropwise at −40° C. The mixture was stirred at −78° C. for 30 min andacetyl chloride (0.17 mL, 2.33 mmolo) was added dropwise. Then themixture was slowly warmed to RT and stirred for 10 h. The mixture waspoured slowly to saturated aq. NH₄Cl and extracted with EA (30 mL*3).The combined organic phase was washed with brine, dried over anhydrousMgSO₄ and concentrated in vacuo to get the desired product as a yellowoil (0.40 g, 88% yield). LC-MS: m/z 245.2 (M+H)⁺.

Step C:5-methyl-2,3-diphenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (100 mg, 0.42 mmol) andmethyl methyl 3-oxo-2-(quinoxalin-6-yl)butanoate (135 mg, 0.55 mmol) inAcOH (5 mL) was stirred at 100° C. for 1 h. After removal of AcOH, 10%of NaHCO₃ was added to afford the desired product.

¹H NMR (DMSO-d₆) δ: 12.05 (br. s., 1H), 8.95 (dd, J=1.6 Hz, 2.0 Hz, 2H),8.12 (d, J=8.8 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.90 (dd, J=1.6 Hz, 2.0Hz, 1H), 7.51 (dd, J=3.6 Hz, 2.4 Hz, 2H), 7.44-7.28 (m, 8H), 2.26 (s,3H). LC-MS: m/z 430.0 (M+H)⁺.

Compound 332

Step D:N,N-dimethyl-2-(4-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)acetamide

To a solution of Intermediate 4 (80 mg, 0.2 mmol, Compound 237) in DMF(5 mL) were added 2-bromo-N,N-dimethylacetamide (34 mg, 0.2 mmol) andK₂CO₃ (56 mg, 0.4 mmol). The mixture was stirred at 60° C. for 3 h. Themixture was poured into H₂O (15 mL) and extracted with DCM (3*10 mL).The combined extracts were washed with brine and dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford the title compound 5.

¹H NMR (DMSO-d₆) δ: 11.88 (br. s., 1H), 7.39-7.49 (m, 5H), 7.28-7.38 (m,5H), 7.23 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.84 (s, 2H), 3.03(s, 3H), 2.87 (s, 3H), 2.18 (s, 3H). LC-MS: m/z 480.0 (M+H)⁺.

Compound 333

Step A: methyl 2-(6-methoxypyridin-3-yl)acetate

To 2-(6-methoxypyridin-3-yl)acetic acid (1.0 g, 5.98 mmol) in MeOH (20mL) was slowly added thionyl chloride (4.0 mL, 55.1 mmol) at −10° C.,and the mixture was stirred at RT overnight. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in DCM. Thesolution was washed with saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by flashchromatography, eluting with PE/EA=4/1, to obtain the desired product asyellow oil (1.0 g, 92% yield). LC-MS: m/z 182.2 (M+H)⁺.

Step B: methyl 2-(6-methoxypyridin-3-yl)-3-oxobutanoate

To a solution of methyl 2-(6-methoxypyridin-3-yl)acetate (0.5 g, 2.76mmol) in THF (20 mL) was added LDA (2.0 M in THF, 1.8 mL, 3.58 mmol)dropwise at −78° C. The mixture was stirred at −78° C. for 30 min andacetyl chloride (0.2 mL, 3.31 mmol) was added dropwise. Then the mixturewas slowly warmed to RT and stirred for 10 min. The mixture was pouredslowly to saturated aq. NH₄Cl and extracted with EA (30 mL*3). Thecombined organic phase was washed with brine, dried over anhydrous MgSO₄and concentrated in vacuo to get the desired product as a yellow oil(0.76 g, crude) which was directly used to the next step without furtherpurification. LC-MS: m/z 224.2 (M+H)⁺.

Step C:6-(6-methoxypyridin-3-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (150 mg, 1.06 mmol) andmethyl 2-(6-methoxypyridin-3-yl)-3-oxobutanoate (309 mg, 1.38 mmol) inAcOH (5 mL) was stirred at 100° C. for 1 h. After removal of AcOH underreduced pressure, 10% of NaHCO₃ was added to afford the desired product.

¹H NMR (DMSO-d₆) δ: 12.01 (br. s., 1H), 8.13 (d, J=2.4 Hz, 1H), 7.70(dd, J=2.4 Hz, 2.4 Hz, 1H), 7.47-7.42 (m, 5H), 7.33 (dd, J=1.6 Hz, 1.6Hz, 5H), 6.91 (dd, J=0.4 Hz, 0.4 Hz, 1H), 3.91 (s, 3H), 2.22 (s, 3H).LC-MS: m/z 409.4 (M+H)⁺.

Compound 334

Step A: methyl 2-(benzofuran-5-yl)acetate

To a solution of 2-(benzofuran-5-yl)acetic acid (350 mg, 2 mmol) in MeOH(40 mL) was added one drop of concentrated H₂SO₄. The mixture wasrefluxed for 3 h. Then the mixture was cooled to r.t. and evaporated.The residue was dissolved in EA (30 mL), washed with 10% NaHCO₃ aqueoussolution and brine, dried over anhydrous MgSO₄, and concentrated invacuo to afford the intermediate 2 as a colorless oil (340 mg, 90%yield) which was used to the next step without purification. LC-MS: m/z191.0 (M+H)⁺.

Step B: methyl 2-(benzofuran-5-yl)-3-oxobutanoate

To a solution of Intermediate 2 (340 mg, 1.8 mmol) in THF (20 mL) wasadded LDA (2 mol/L in THF, 1.1 mL) at −40° C. dropwise. After themixture was stirred at −40° C. for 30 min, acetyl chloride (173 mg, 2.2mmol) was added dropwise. The mixture was then stirred at r.t. for 3 h.The mixture was diluted with EA (20 mL) and quenched with saturatedNH₄Cl aqueous solution. The organic phase was separated and washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to affordthe crude intermediate 3 as a yellow oil (250 mg, 60% yield) which wasused to the next step without purification. LC-MS: m/z 233.0 (M+H)⁺.

Step C:6-(benzofuran-5-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (110 mg, 0.47 mmol) and3,4-diphenyl-1H-pyrazol-5-amine (120 mg, 0.51 mmol) in AcOH (10 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. toafford the desired product 4.

¹H NMR (DMSO-d₆) δ: 11.94 (br. s., 1H), 8.04 (d, J=2.0 Hz, 1H), 7.65 (d,J=8.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.38-7.48 (m, 5H), 7.31-7.37 (m,5H), 7.25 (dd, J=8.4, 1.6 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 2.17 (s, 3H).LC-MS: m/z 418.0 (M+H)⁺.

Compound 335

Step A: ethyl 2-(3-bromo-4-nitrophenyl)-3-oxobutanoate

2-bromo-4-fluoro-1-nitrobenzene (6.6 g, 30 mmol), ethyl 3-oxobutanoate(7.8 g, 60 mmol) and K₂CO₃ (12.46 g, 90 mmol) in DMSO (50 mL) wasstirred at 60° C. for 16 h. The mixture was acidified with 1M HCl topH=7 and extracted with EA (50 mL*3). The organic layer was dried andconcentrated to give the crude product, which was purified by silica gelchromatography (PE/EA=3/1) to obtain the desired product as yellow solid(7.6 g, 77% yield). LC-MS: m/z 331.2 (M+H)⁺.

Step B:6-(3-bromo-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of 3,4-diphenyl-1H-pyrazol-5-amine (4.6 g, 19.6 mmol) andethyl 2-(3-bromo-4-nitrophenyl)-3-oxobutanoate (7.2 g, 21.8 mmol) inAcOH (20 mL) was refluxed for 30 min under N₂ protection. The mixturewas cooled to the RT, concentrated and neutralized with saturated sodiumhydrogen carbonate solution to adjust to pH=7. The precipitates werecollected by filtration, washed with petroleum ether and dried to obtainthe desired product as a yellow solid (9.0 g, 92% yield). LC-MS: m/z502.2 (M+H)⁺.

Step C:5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-(3-bromo-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(3.0 g, 6.0 mmol), ethynyltrimethylsilane (1.18 g, 12.0 mmol),Pd(PPh₃)₂Cl₂ (42 mg, 0.6 mmol), CuI (228 mg, 1.2 mmol) and TEA (15 mL,18.0 mmol) in THF (50 ml) was heated to 50° C. for 6 h under anatmosphere of N₂. The mixture was cooled to the RT, diluted with water,and extracted with EA (30 mL*3). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by silica gel column, eluting withDCM/MeOH (40/1), to obtain the desired product as a yellow solid (2.3 g,74% yield). LC-MS: m/z 519.2 (M+H)⁺.

Step D:6-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a suspension of5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(2.3 g, 4.4 mmol) in DMF/MeOH (20 mL/30 mL) was added sat. ammoniumchloride aqueous solution (20 mL) and zinc powder (2.88 g, 44.4 mmol).The resultant mixture was stirred at RT overnight. The reaction mixturewas filtered and concentrated. The residue was purified by flash columnchromatography, eluting with DCM/MeOH (20/1), to obtain the desiredproduct as a yellow solid (600 mg, 28% yield). LC-MS: m/z 489.2 (M+H)⁺.

Step E:5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(120 mg, 0.24 mmol) in acetonitrile/water (1.4 mL/0.7 mL) was added con.hydrochloric acid (0.2 mL, 2.4 mmol) at 0° C. Then a solution of sodiumnitrite (25 mg, 0.37 mmol) in water (2 mL) was introduced slowly whilekeeping the temperature below 0° C. After the addition, the resultantmixture was stirred at 0° C. for 30 min. Then the mixture was addedslowly to a stirred solution of piperidine (137 mg, 1.62 mmol) andpotassium carbonate (260 mg, 1.88 mmol) in acetonitrile/water (2 mL/1mL) at 0° C. The resultant mixture was allowed to warm to RT for 1 h.The reaction was quenched with water, extracted with EA (30 mL*3). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby silica gel column, eluting with DCM/MeOH (20/1), to obtain thedesired product as a yellow solid (140 mg, 99% yield). LC-MS: m/z 585.3(M+H)⁺.

Step F:6-(3-ethynyl-4-(piperidin-1-yldiazenyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a mixture of5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.08 mmol) in THF/MeOH (0.85 ml/0.17 mL) was added potassiumcarbonate (117 mg, 0.85 mmol) and potassium hydroxide (50 mg, 0.09mmol). Then the mixture was stirred at RT for 2 h, The reaction mixturewas diluted with water, extracted with EA (30 mL*3). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column, eluting with DCM/MeOH (25/1), to obtain the desired productas a yellow solid (30 mg, 50% yield). LC-MS: m/z 513.2 (M+H)⁺.

Step G:6-(cinnolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of6-(3-ethynyl-4-(piperidin-1-yldiazenyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(30 mg, 0.006 mmol) in 1,2-dichlorobenzen (2 mL) was heated at 200° C.for 16 h to obtain the desired product.

¹H NMR (DMSO-d₆) δ: 12.05 (br. s., 1H), 9.38 (d, J=5.6 Hz, 1H), 8.48 (d,J=8.4 Hz, 1H), 8.23 (d, J=6.0 Hz, 1H), 8.05 (s, 1H), 7.98 (dd, J=2.0 Hz,1.6 Hz, 1H), 7.48-7.31 (m, 10H), 2.27 (s, 3H). LC-MS: m/z 430.2 (M+H)⁺.

Compound 336

Step A: 5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (3 g, 12.8 mmol, 1 eq.)and methyl 3-oxobutanoate (2.96 g, 25.5 mmol) in AcOH (20 mL) wasstirred at 120° C. for 4 h. Then the mixture was cooled to r.t. andfiltered to give the crude solid which was washed with EA to afford thedesired product 5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(3.5 g) LC-MS: m/z 302.1 (M+H)⁺.

Step B:5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

To the mixture of5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (3.5 g, 11.6mmol), Cs₂CO₃ (7.58 g, 23.2 mmol) in DMF (50 mL) was added1-(chloromethyl)-4-methoxybenzene (2.3 g, 13.9 mmol). The reaction wasstirred at r.t. for 16 h. The mixture was diluted with H₂O (30 mL) andextracted with DCM (10 mL*3). The organic layer was dried over anhydroussodium sulfate and concentrated in vacuo to dryness. The resulting solidwas purified by silica gel chromatography (PE/EA=10:1) to give thedesired product (3.19 g). LC-MS: m/z 432.3 (M+H)⁺.

Step C:6-bromo-5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

To a solution of5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(3.1 g, 7.2 mmol) in DCM (50 mL) and TEA (1.45 g, 14.58 mmol) was addeddropwise NBS (1.4 g, 7.9 mmol) in DCM (5 mL). The resultant mixture wasstirred for 3 hours at ambient temperature and washed with water. Theaqueous phase was extracted with DCM (20 mL). The combined organiclayers were washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by silicagel chromatography (PE/EA=10/1) to obtain the6-bromo-5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(3 g, 82% yield). LC-MS: m/z 510.1 (M+H)⁺.

Step D:5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one

To a solution of6-bromo-5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one(400 mg, 0.786 mmol) and 1,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid(251 mg, 0.943 mmol) in dioxane/H₂O (26 mL/9 mL) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (57 mg, 0.078 mmol) and sodium carbonate (166mg, 1.57 mmol). The reaction mixture was then refluxed under nitrogenatmosphere overnight. The reaction mixture was filtered and concentratedin vacuo. The residue was purified by column chromatography (PE/EA=1/20)to afford5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (100 mg, 22.3% yield)as a white solid. LC-MS: m/z 570.2 (M+H)⁺.

Step E: Compound 336:5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one 100 mg, 0.176 mmol) inHCl/dioxane (1.5 mL, 4M) was stirred at r.t. for 1 h. The mixture wasconcentrated in vacuo to dryness. The resulting residue was dissolved in4N HCl and THF (10 mL) and stirred at r.t. for 1 h to afford5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.81 (br. s., 1H), 7.39-7.48 (m, 5H), 7.28-7.35 (m,5H), 5.65-5.74 (m, 1H), 3.02 (br. s., 2H), 2.53-2.70 (m, 4H), 2.33 (s,3H). LC-MS: m/z 396.1 (M+H)⁺.

Compound 337

Step A:6-(4-hydroxycyclohex-1-en-1-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 336, 20 mg, 0.05 mmol) in MeOH (10mL) was added NaBH₄ (2.3 mg, 0.06 mmol). The reaction mixture wasstirred at r.t. for 1 h. The mixture was poured into water and extractedwith EA (10 mL×3). The combined organic phase was washed with brine,dried over anhydrous sodium sulfate and concentrated in vacuo to afford6-(4-hydroxycyclohex-1-en-1-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 11.71 (br. s., 1H), 7.37-7.46 (m, 5H), 7.24-7.35 (m,6H), 5.48 (br. s., 1H), 4.69 (d, J=4.03 Hz, 1H), 3.82 (br. s., 1H),2.29-2.43 (m, 2H), 2.27 (s, 4H), 1.96-2.08 (m, 1H), 1.82-1.93 (m, 1H),1.55-1.68 (m, 1H). LC-MS: m/z 398.2 (M+H)⁺.

Compound 338 and Compound 339

Step D:5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

To a suspension of5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(88 g, 0.208 mol, Compound 221) in DCM (500 mL) was added SOCl₂ (120 mL)with a funnel. The mixture was stirred at room temperature for 1 hour.The precipitates were filtered, washed with ethyl acetate, and driedunder vacuum to give5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(110 g) as an off-white solid which was directly used to the next stepwithout further purification.

Step E: Compound 338 and Compound 339:5-((1H-tetrazol-1-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneand5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(200 mg, 0.453 mmol), 1H-tetrazole (63.4 mg, 0.905 mmol), and TEA (229mg, 2.263 mmol) in DMF (5 mL) was stirred at 40° C. overnight. Themixture was concentrated under reduced pressure to afford5-((1H-tetrazol-1-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-oneand5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Compound 338:5-((1H-tetrazol-1-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (br. s., 1H), 7.19-7.44 (m, 4H),7.07-7.18 (m, 5H) 6.85-7.07 (m, 5H), 6.36-6.82 (m, 1H), 5.74-5.93 (m,2H), 3.80 (s, 3H). LC-MS: m/z 476.1 (M+H)⁺.

Compound 339:5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

¹H NMR (400 MHz, TFA) δ: 9.32 (br. s., 1H), 7.61 (br. s., 6H), 7.51 (br.s., 2H), 7.32-7.47 (m, 4H), 7.25 (br. s., 2H), 5.99 (br. s., 2H), 4.08(br. s., 3H). LC-MS: m/z 476.0 (M+H)⁺.

Compound 340

Step F: (S)-tert-butyl(1-(((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

To a solution of Intermediate 6 (Compound 222, 200 mg, 0.45 mmol) in DMF(8 mL) were added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoicacid (117 mg, 0.54 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (258 mg, 0.68 mmol) and N,N-diisopropylethylamine(116 mg, 0.9 mmol). The mixture was stirred at r.t. overnight. Themixture was diluted with H₂O (30 ml) and extracted with DCM (3*30 mL).The extracts were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=20:1) to afford the title compound 7 as a white solid (230 mg,82% yield). LC-MS: m/z 622.2 (M+H)⁺.

Step G:(S)-2-amino-N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)-3-methylbutanamide

A solution of Intermediate 7 (180 mg, 0.29 mmol) in 4M HCl in1,4-dioxane (8 mL) was stirred at 0° C. r.t. for 1 h and then at r.t.for 3 h. Solvent and other volatiles were removed in vacuo. The residuewas dissolved in MeOH (10 mL) and treated with NaHCO₃(2 mol/L, 10 mL) toafford the title compound 8.

¹H NMR (DMSO-d₆) δ: 8.45 (br. s., 1H), 7.50 (t, J=8.2 Hz, 4H), 7.31 (br.s., 3H), 7.18-7.27 (m, 4H), 7.07-7.12 (m, 1H), 6.94 (d, J=8.6 Hz, 2H),4.18 (d, J=15.6 Hz, 1H), 3.91 (d, J=15.6 Hz, 1H), 3.79 (s, 3H), 3.52 (d,J=5.0 Hz, 1H), 2.06 (dd, J=12.4, 6.6 Hz, 1H), 0.91 (d, J=6.8 Hz, 3H),0.85 (d, J=6.8 Hz, 3H). LC-MS: m/z 522.2 (M+H)⁺.

Compound 341

Step A:5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

A solution of3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 279, 47.0 g, 104 mmol) in phosphorusoxychloride (100 mL) was stirred at reflux for 16 hrs. The solvent wasremoved invacuo. The residue was added slowly to methanol (100 mL)cooled at 0° C. The precipitates were collected by filtration, washedwith methanol, and dried under reduced pressure to give5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(50 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 1.70 (d, J=4.57 Hz, 4H) 2.20 (br. s., 4H) 3.84 (s,4H) 5.87 (br. s., 1H) 7.10 (d, J=8.60 Hz, 2H) 7.36-7.56 (m, 5H) 7.82 (d,J=7.25 Hz, 2H). LC-MS: m/z 450.2 (M+H)⁺.

Step B:5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine

To a solution of5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(40 g, 88 mmol) in dichloromethane (400 ml) at 0° C. was added sodiummethoxide (30% in methanol, 80 g) dropwise. The resultant mixture wasstirred for 10 min at 0° C. The reaction was quenched by adding icewater (100 mL) and extracted with dichloromethane (200 mL) three times.The combined organic layers were washed with brine (200 ml), dried overanhydrous sodium sulfate, and concentrated invacuo. The residue wassuspended in MeOH (50 mL). The precipitates were collected byfiltration, washed with MeOH, and dried under reduced pressure to give5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(36 g) as a yellow solid.

¹H NMR (DMSO-d₆): δ 7.78-7.91 (m, 2H), 7.42-7.58 (m, 3H), 7.33-7.42 (m,J=8.9 Hz, 2H), 7.00-7.14 (m, J=8.9 Hz, 2H), 5.83 (br. s., 1H), 4.14 (s,3H), 3.84 (s, 3H), 2.20 (d, J=5.9 Hz, 4H), 1.61-1.77 (m, 4H). LC-MS: m/z446.1 (M+H)⁺.

Step C:N-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine

A mixture of5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine(200 mg, 0.45 mmol), isoxazol-3-amine (113.4 mg, 1.35 mmol), andpalladium diacetate (10.1 mg, 0.045 mmol), Xantphos (52 mg, 0.09 mmol)and sodium carbonate (143 mg, 1.35 mmol) in 1,4-dioxane (50 mL) washeated at 110° C. for 12 hours under nitrogen atmosphere. The mixturewas filtered through celite and the filtrate was concentrated in vacuo.The residue was purified by flash chromatography to afford the desiredproductN-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amine.

¹H NMR (DMSO-d₆) δ: 8.84 (d, J=1.61 Hz, 1H), 8.30 (s, 1H), 7.74-7.82 (m,2H), 7.35-7.55 (m, 5H), 7.28 (d, J=1.61 Hz, 1H), 7.07-7.16 (m, 2H), 5.83(s, 1H), 4.08 (s, 3H), 3.86 (s, 3H), 2.25 (br. s., 2H), 2.19 (br. s.,2H), 1.70 (d, J=4.84 Hz, 4H). LC-MS: m/z 493.9 (M+H)⁺.

Compound 342

Step A: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(Synthesized in Scheme of Compound 101, 300 mg, 0.68 mmol),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-amine (230 mg, 1.36mmol), Pd(OAc)₂ (30.5 mg, 0.14 mmol), Xantphos (118 mg, 0.20 mmol) andCs₂CO₃ (487 mg, 1.49 mmol) in 1,4-dioxane (10 ml) was reacted at 100° C.for 45 min under N₂ atmosphere in a microwave reactor. The reaction wasthen cooled to RT and filtered. The dark filtrate was concentrated invacuo and purified by flash column chromatography, eluting withDCM/MeOH=40:1, to get the desired product as a yellow solid (110 mg, 26%yield). LC-MS: m/z 619.5 (M+H)⁺.

Step B:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine

The7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine(110 mg, 0.18 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 60° C.for 1 h. Then the mixture was concentrated to give the crude product,which was added into ammonia water (5 mL) and stirred on for 1 h toafford the desired product.

1H NMR (DMSO-d₆) δ: 8.20 (s, 1H), 7.44-7.30 (m, 14H), 7.15 (d, J=8.0 Hz,2H), 3.88 (s, 3H), 3.74 (s, 3H). LC-MS: m/z 489.0 (M+H)⁺.

Compound 343

Step E: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(600 mg, 1.36 mmol, Synthesized in Scheme of Compound 101),1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (580 mg, 2.72mmol), Pd(OAc)₂ (61 mg, 0.27 mmol), xantphos (197 mg, 0.34 mmol) andCs₂CO₃ (890 mg, 2.72 mmol) in 1,4-dioxane (5 mL) was stirred at 120° C.through microwave irradiation for 1 hour under N₂ atmosphere. Themixture was filtered through celite and the filtrate was concentrated invacuo. The residue was purified by flash chromatography to afford the7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(150 mg) as a yellow solid. LC-MS: m/z 619.0 (M+H)⁺.

Step F: Compound 343:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

To a solution of7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(150 mg, 0.243 mmol) in DCM (5 mL) was added TFA (2 mL), the mixture wasstirred at room temperature for 3 h. The mixture was concentrated underreduced pressure. The residue was dissolved in ammonium hydroxide (3 mL)and stirred at room temperature overnight. The mixture was thenconcentrated to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.34 (br. s., 1H), 7.63 (br. s., 1H), 7.58(d, J=3.49 Hz, 2H), 7.47 (d, J=8.33 Hz, 2H), 7.51 (d, J=7.52 Hz, 2H),7.34-7.44 (m, 5H), 7.12-7.32 (m, 4H), 6.88 (br. s., 1H), 4.09 (s, 3H),3.87 (s, 3H). LC-MS: m/z 488.9 (M+H)⁺.

Compound 344

Step A: chloromethyl dimethylcarbamate

To a solution of chloromethyl carbonochloridate (500 mg, 3.9 mmol) inTHF (30 mL) was added dimethylamine (2 mol/L in THF, 3.9 mL) dropwise at0° C. under vigorous stirring. Then the mixture was stirred at r.t.overnight. The mixture was evaporated. The residue was stirred intoluene (5 mL) and filtered. The filtrate was washed with 10% NaHCO₃aqueous solution, water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the title compound 2 as a yellow oil(400 mg, 75 yield) which was used to the next step without furtherpurification.

¹H NMR (DMSO-d₆) δ: 5.79 (s, 2H), 2.98 (s, 3H), 2.96 (s, 3H).

Step B:((3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)oxy)methyldimethylcarbamate

To a solution of3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Compound 212, 50 mg, 0.12 mmol) in DMF (3 mL) were added chloromethyldimethylcarbamate (54 mg, 0.36 mmol) and K₂CO₃ (50 mg, 0.36 mmol). Themixture was stirred at 60° C. for 10 h. The mixture was poured into H₂O(15 mL) and extracted with DCM (3*10 mL). The combined extracts werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuoto afford the title compound 3.

¹H NMR (DMSO-d₆) δ: 7.79-7.85 (m, 2H), 7.45-7.52 (m, 2H), 7.39-7.45 (m,1H), 7.19-7.25 (m, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.04 (s, 2H), 5.79 (dt,J=3.4, 2.0 Hz, 1H), 3.82 (s, 3H), 2.71 (s, 3H), 2.63 (s, 3H), 2.29 (s,3H), 2.23-2.28 (m, 2H), 2.13-2.19 (m, 2H), 1.62-1.76 (m, 4H). LC-MS: m/z513.1 (M+H)⁺.

Compound 345

Step A:7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,3,5-triazin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(800 mg, 1.81 mmol), ethyl 1,3,5-triazin-2-amine (Synthesized in Schemeof Compound 101, 348 mg, 3.62 mmol), and Pd(OAc)₂ (81 mg, 0.36 mmol),Xantphos (260 mg, 0.45 mmol) and Na₂CO₃ (384 mg, 3.62 mmol) in1.4-dioxane (15 mL) was heated at 110° C. for 4 hours under N₂atmosphere. The mixture was filtered through celite, and the filtratewas concentrated in vacuo to afford the title product.

¹H NMR (DMSO-d₆) δ: 10.42 (s, 1H), 8.51 (s, 2H), 7.57-7.63 (m, 2H),7.36-7.49 (m, 7H), 7.28-7.33 (m, 3H), 6.87-6.95 (m, 2H), 4.20 (s, 3H),3.74 (s, 3H). LC-MS: m/z 502.0 (M+H)⁺.

Compound 346

Step A: 3-(3-chlorophenyl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (975 mg, 8.3 mmol) in THF (40 mL)was added lithium diisopropylamide (2.0 mol/L in THF, 5 mL, 10.0 mmol)at −78° C. After the mixture was stirred at −78° C. for 30 min,3-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. Then themixture was stirred at r.t. for 2 h. The mixture was diluted with EA (30mL) and quenched with saturated NH₄Cl. The organic phase was separatedand washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was washed with PE to afford the desired intermediate2 as a white solid (1.2 g, 57% yield). LC-MS: m/z 256.0/258.0 (M+H)⁺.

Step B: 3-(3-chlorophenyl)-4-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 2 (500 mg, 2.0 mmol) and hydrazine hydrate(200 mg, 4.0 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (20 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the water phase was extracted with EA (10 mL*3).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford the crude desiredintermediate 3 as a yellow oil (500 mg, 95% yield) which was used to thenext step without purification. LC-MS: m/z 270.0/272.0 (M+H)⁺.

Step C:2-(3-chlorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (200 mg, 0.7 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate (270 mg, 1.1 mmol) in AcOH (10 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (15 mL) and neutralized with10% NaHCO₃. The organic phase was separated, and the water phase wasextracted with EA (15 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to affordthe desired product 4.

¹H NMR (DMSO-d₆) δ: 12.15 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.40(d, J=7.4 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.75(dd, J=8.6, 1.8 Hz, 1H), 7.57 (dd, J=8.2, 4.2 Hz, 1H), 7.40-7.53 (m,5H), 7.33-7.40 (m, 4H), 2.25 (s, 3H). LC-MS: m/z 463.0/465.0 (M+H)⁺.

Compound 347

Step A: 3-(4-chlorophenyl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (975 mg, 8.3 mmol) in THF (40 mL)was added lithium diisopropylamide (2.0 mol/L in THF, 5 mL, 10.0 mmol)at −78° C. After the mixture was stirred at −78° C. for 30 min,4-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. Then themixture was stirred at r.t. for 2 h. The mixture was diluted with EA (30mL) and quenched with saturated NH₄Cl. The organic phase was separatedand washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was washed with PE to afford the desired intermediate2 as a white solid (1.3 g, 61% yield). LC-MS: m/z 256.0/258.0 (M+H)⁺.

Step B: 3-(4-chlorophenyl)-4-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 2 (500 mg, 2.0 mmol) and hydrazine hydrate(200 mg, 4.0 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (20 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the the water phase was extracted with EA (10mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford the crude desiredintermediate 3 as a yellow oil (500 mg, 95% yield) which was used to thenext step without purification. LC-MS: m/z 270.0/272.0 (M+H)⁺.

Step C:2-(4-chlorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (80 mg, 0.3 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate (108 mg, 0.5 mmol) in AcOH (5 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (10 mL) and neutralized with10% NaHCO₃. The organic phase was separated and the water phase wasextracted with EA (10 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to affordthe desired product 4.

¹H NMR (DMSO-d₆) δ: 12.10 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.39(d, J=7.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.74(dd, J=8.6, 1.8 Hz, 1H), 7.57 (dd, J=8.2, 4.2 Hz, 1H), 7.44-7.52 (m,3H), 7.40-7.44 (m, 4H), 7.34-7.38 (m, 2H), 2.24 (s, 3H). LC-MS: m/z463.0/465.0 (M+H)⁺.

Compound 348

Step A: 3-oxo-2-phenyl-3-(pyridin-4-yl)propanenitrile

To the mixture of methyl isonicotinate (1.4 g, 10 mmol) and2-phenylacetonitrile (1.2 g, 10 mmol) in THE (50 mL) was added sodiumhydride (480 mg, 60% content, 12 mmol) at r.t. The mixture was refluxedovernight. The mixture was diluted with EA (50 mL) and quenched withsaturated NH₄Cl. The organic phase was separated and washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography to afford the desired intermediate 2 asa light yellow solid (800 mg, 36% yield). LC-MS: m/z 223.1 (M+H)⁺.

Step B: 4-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine

The mixture of Intermediate 2 (500 mg, 2.3 mmol) and hydrazine hydrate(230 mg, 4.6 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (15 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the the water phase was extracted with EA (15mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford the desiredintermediate 3 as a yellow solid (250 mg, 46% yield) which was used tothe next step without purification. LC-MS: m/z 237.1 (M+H)⁺.

Step C:5-methyl-3-phenyl-2-(pyridin-4-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (100 mg, 0.42 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate (150 mg, 0.64 mmol) in AcOH (10 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (10 mL) and neutralized with10% NaHCO₃. The organic phase was separated and the water phase wasextracted with EA (10 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to affordthe desired product 4.

¹H NMR (DMSO-d₆) δ: 12.22 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.54(d, J=4.6 Hz, 2H), 8.36-8.43 (m, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.97 (d,J=1.8 Hz, 1H), 7.75 (dd, J=8.6, 2.0 Hz, 1H), 7.58 (dd, J=8.2, 4.2 Hz,1H), 7.44-7.54 (m, 3H), 7.36-7.42 (m, 4H), 2.25 (s, 3H). LC-MS: m/z430.1 (M+H)⁺.

Compound 349

Step A: 3-(6-methoxypyridin-3-yl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (1.0 g, 8.54 mmol) in THF (20 mL)was added LiHMDS (5.1 mL, 10.2 mmol, 2.0 M in THF) at −78° C. dropwise.After addition, the mixture was stirred at −78° C. for 1 hour. Thenmethyl 6-methoxynicotinate (1.43 g, 8.54 mmol) was added dropwise. Thereaction was slowly warmed to room temperature and stirred for 12 hours.The reaction was quenched by adding saturated NH₄Cl (50 mL), extractedwith ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL),dried over anhydrous sodium sulfate, filtered and concentrated to obtainthe title compound (crude, 2 g) which was directly used in the next stepwithout further purification.

Step B: 3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine

A mixture of 3-(6-methoxypyridin-3-yl)-3-oxo-2-phenylpropanenitrile (2g, crude) and NH₂NH₂ (2.37 g, 43.8 mmol) in EtOH/AcOH (20 mL/5 mL) wasstirred at 100° C. for 8 hours. After cooling to room temperature, themixture was concentrated by vacuum. The residue was diluted with EtOAc(20 mL), washed with saturated NaHCO₃(20 mL) and brine (20 mL), driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash column (petroleum ether/ethyl acetate=3:1) to obtain3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine (150 mg) as ayellow solid. LC-MS: m/z 267.0 (M+H)⁺.

Step C: Compound 349:2-(6-methoxypyridin-3-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine (150mg, 0.564 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (137 mg,0.564 mmol) in AcOH (5 mL) and dioxane (1 mL) was stirred at 100° C.overnight to obtain the title compound.

¹H NMR (DMSO-d₆) δ: 12.11 (s, 1H), 8.95 (dd, J=4.16, 1.75 Hz, 1H),8.37-8.44 (m, 1H), 8.11-8.15 (m, 1H), 8.08 (d, J=8.60 Hz, 1H), 7.97 (d,J=1.61 Hz, 1H), 7.77-7.80 (m, 1H), 7.75 (dd, J=8.73, 2.01 Hz, 1H), 7.58(dd, J=8.19, 4.16 Hz, 1H), 7.49-7.54 (m, 2H), 7.43-7.48 (m, 1H),7.37-7.42 (m, 2H), 6.84 (d, J=8.60 Hz, 1H), 3.85 (s, 3H), 2.25 (s, 3H).LC-MS: m/z 460.1 (M+H)⁺.

Compound 350

Step A: 3-(2-chloropyridin-4-yl)-3-oxo-2-phenylpropanenitrile

To a solution of 2-phenylacetonitrile (1.2 g, 10 mmol) and methyl2-chloroisonicotinate (1.7 g, 10.0 mmol) in THF (50 mL) was added sodiumhydride (480 mg, 60% content, 12 mmol) at r.t. The mixture was refluxedfor 5 h. The mixture was diluted with EA (50 mL) and quenched withsaturated NH₄Cl. The organic phase was separated and washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by flash chromatography to afford the intermediate 2 as ayellow solid (800 mg, 31% yield). LC-MS: m/z 257.0/259.0 (M+H)⁺.

Step B: 3-(2-chloropyridin-4-yl)-4-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 2 (350 mg, 1.4 mmol) and hydrazine hydrate(140 mg, 2.8 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (10 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the the water phase was extracted with EA (10mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography (PE/EA=3:1) to afford the crude intermediate 3 as ayellow solid (40 mg, 11% yield). LC-MS: m/z 271.0/273.0 (M+H)⁺.

Step C:2-(2-chloropyridin-4-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 3 (40 mg, 0.15 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate (54 mg, 0.22 mmol) in AcOH (5 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (10 mL) and neutralized with10% NaHCO₃. The organic phase was separated and the water phase wasextracted with EA (10 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to affordthe desired product 4.

¹H NMR (DMSO-d₆) δ: 12.26 (s, 1H), 8.95 (br. s., 1H), 8.35-8.43 (m, 2H),8.09 (d, J=8.6 Hz, 1H), 7.93-8.00 (m, 1H), 7.75 (dd, J=8.6, 1.6 Hz, 1H),7.47-7.62 (m, 4H), 7.36-7.46 (m, 4H), 2.25 (s, 3H). LC-MS: m/z464.0/466.0 (M+H)⁺.

Compound 351

Step A: Methyl 2-methoxyisonicotinate

To a solution of methyl 2-chloroisonicotinate (1.7 g, 10 mmol) in MeOH(30 mL) was added Sodium methoxide (1.1 g, 20 mmol). The resultantmixture was refluxed overnight. The mixture was then treated with HCl (2mol/L) until pH=7 and evaporated. The residue was dissolved in EA (50mL), washed with H₂O and brine, dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyto afford the intermediate 2 as a white solid (1.2 g, 72% yield).

¹H NMR (CHLOROFORM-d) δ: 8.26-8.30 (m, 1H), 7.40 (dd, J=5.1, 1.2 Hz,1H), 7.30-7.33 (m, 1H), 3.97 (s, 3H), 3.94 (s, 3H). LC-MS: m/z 168.0(M+H)⁺.

Step B: 3-(2-methoxypyridin-4-yl)-3-oxo-2-phenylpropanenitrile

To the mixture of Intermediate 2 (860 mg, 5.1 mmol) and2-phenylacetonitrile (730 mg, 6.2 mmol) in THF (20 mL) was added NaHMDS(2.0 mol/L in THF, 3.1 mL) dropwise at 0° C. The mixture was at 0° C.for 30 min and then stirred at r.t. overnight. The mixture was dilutedwith EA (30 mL) and quenched with saturated NH₄Cl. The organic phase wasseparated and washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyto afford the intermediate 3 as a light yellow solid (640 mg, 50%yield).

¹H NMR (METHANOL-d₄) δ: 8.08-8.11 (m, 1H), 7.88-7.92 (m, 2H), 7.23 (t,J=7.8 Hz, 2H), 7.15 (dd, J=5.0, 1.2 Hz, 1H), 6.97-7.02 (m, 2H), 3.92 (s,3H). LC-MS: m/z 253.1 (M+H)⁺.

Step C: 3-(2-methoxypyridin-4-yl)-4-phenyl-1H-pyrazol-5-amine

The mixture of Intermediate 3 (320 mg, 1.3 mmol) and hydrazine hydrate(130 mg, 2.6 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2 h.Then the mixture was cooled to r.t. and evaporated. The residue wasdissolved in EA (10 mL) and neutralized with 10% NaHCO₃. The organicphase was separated and the the water phase was extracted with EA (10mL*3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography (PE/EA 3:1) to afford the crude intermediate 4 as ayellow solid (250 mg, 74% yield). LC-MS: m/z 267.1 (M+H)⁺.

Step D:2-(2-methoxypyridin-4-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of Intermediate 4 (250 mg, 0.94 mmol) and methyl3-oxo-2-(quinolin-6-yl)butanoate (340 mg, 1.4 mmol) in AcOH (8 mL) wasstirred at 100° C. for 1 h. Then the mixture was cooled to r.t. andevaporated. The residue was dissolved in EA (15 mL) and neutralized with10% NaHCO₃. The organic phase was separated and the water phase wasextracted with EA (15 mL*3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to affordthe desired product 5.

¹H NMR (DMSO-d₆) δ: 12.18 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.39(d, J=7.4 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.96(d, J=1.8 Hz, 1H), 7.74 (dd, J=8.6, 2.0 Hz, 1H), 7.57 (dd, J=8.2, 4.2Hz, 1H), 7.45-7.55 (m, 3H), 7.37-7.42 (m, 2H), 7.08 (dd, J=5.2, 1.4 Hz,1H), 6.70 (s, 1H), 3.80 (s, 3H), 2.24 (s, 3H). LC-MS: m/z 460.0 (M+H)⁺.

Compound 352

Step A: (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate

A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) andDMF-DMA (4.0 mL) in DMF was stirred at 85° C. for 12 h. After cooling toroom temperature, the mixture was poured into water, extracted withethyl acetate, dried over Na₂SO₄, filtered and concentrated to get thecrude product (3.8 g) which was directly used to the next step withoutfurther purification. LC-MS: m/z 257.3 (M+H)⁺.

Step B: 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.9 mmol) and(E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1mmol) in AcOH (3 mL) was stirred at 100° C. for 2 h. After cooling toroom temperature, the solvent was removed by vacuum, saturated NaHCO₃(6mL) was added, and the precipitate was filtered. The filter cake waswashed with water (2 mL) and MeOH (2 mL) to get2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one asyellow solid (300 mg, 85% yield).

¹H NMR (DMSO-d₆) δ: 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H),8.37-8.47 (m, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.10-8.16 (m, 2H), 8.03-8.10(m, 1H), 7.56 (dd, J=8.3, 4.0 Hz, 1H), 7.45-7.54 (m, 4H), 7.32-7.45 (m,6H). LC-MS: m/z 415.3 (M+H)⁺.

Step C:4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200mg, 0.483 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (173 mg,0.724 mmol) and Cs₂CO₃ (471 mg, 1.448 mmol) in DMF (10 mL) was stirredat 80° C. overnight. After cooling to room temperature, the mixture waspoured into water (20 mL), and extract with EtOAc (3*30 mL). Thecombined organic layers were washed with water (2*30 mL) and brine (30mL), and concentrated under reduce pressure. The residue was purified bycolumn chromatography on silica gel (MeOH:DCM=5:100) to get the titlecompound (130 mg, 47% yield). LC-MS: m/z 573.2 (M+H)⁺.

Step D:4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg, 0.227 mmol) and TBAF (59 mg, 0.227 mmol) in DCM (5 mL) wasstirred at room temperature for 3 h. The mixture was poured into water(20 mL), and the precipitate was filtered. The filter cake was washedwith water (2 mL) and dried to get the title compound (90 mg) as a whitesolid which was used directly in the next step without furtherpurification. LC-MS: m/z 459.1 (M+H)⁺.

Step E:4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(90 mg, 0.2 mol) in DCM (5 mL) was added SOCl₂ (0.5 mL) dropwise. Themixture was stirred at room temperature for 4 hours. The precipitateswere filtered, washed with ethyl acetate, and dried under vacuum to give4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(80 mg) as a off-white solid which was used directly in the next stepwithout further purification. LC-MS: m/z 477.0 (M+H)⁺.

Step F: Compound 352:4-(2-(1H-tetrazol-1-yl)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

To a solution of 1H-tetrazole (29.4 mg, 0.42 mmol) in DMF (10 mL) wasadded NaH (60% dispersion in mineral oil, 12.6 mg, 0.524 mmol) inportions at 0° C. The resulting mixture was stirred at 0° C. for 25 min.4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(50 mg, 0.105 mmol) was then added. The mixture was warmed to 80° C. andstirred for 10 h. After cooling to room temperature, water was added toget the title compound.

¹H NMR (DMSO-d₆) δ: 8.99 (s, 1H), 8.92 (dd, J=4.30, 1.61 Hz, 1H), 8.41(d, J=8.33 Hz, 1H), 8.21 (d, J=1.88 Hz, 1H), 8.17 (s, 1H), 8.09 (d,J=8.87 Hz, 1H), 8.00 (dd, J=8.87, 2.15 Hz, 1H), 7.59 (dd, J=8.19, 4.16Hz, 1H), 7.48 (s, 5H), 7.39-7.43 (m, 2H), 7.30-7.35 (m, 3H), 4.84 (t,J=6.04 Hz, 2H), 4.45 (t, J=5.78 Hz, 2H). LC-MS: m/z 511.1 (M+H)⁺.

Compound 353

Step A1: (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate

A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) andDMF-DMA (4.0 mL) in DMF was stirred at 85° C. for 12 h. After cooling toroom temperature, the mixture was poured into water, extracted withethyl acetate, dried over Na₂SO₄, filtered and concentrated to get thecrude product (3.8 g) which was directly used to the next step withoutfurther purification. LC-MS: m/z 257.3 (M+H)⁺.

Step B 1:2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.9 mmol) and(E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1mmol) in AcOH (3 mL) was stirred at 100° C. for 2 h. After cooling toroom temperature, the solvent was removed by vacuum, saturated NaHCO₃(6mL) was added, and the precipitate was filtered. The filter cake waswashed with water (2 mL) and MeOH (2 mL) to get2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one asyellow solid (300 mg, 85% yield).

¹H NMR (DMSO-d₆) δ: 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H),8.37-8.47 (m, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.10-8.16 (m, 2H), 8.03-8.10(m, 1H), 7.56 (dd, J=8.3, 4.0 Hz, 1H), 7.45-7.54 (m, 4H), 7.32-7.45 (m,6H). LC-MS: m/z 415.3 (M+H)⁺.

Step C1:4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200mg, 0.483 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (173 mg,0.724 mmol) and Cs₂CO₃ (471 mg, 1.448 mmol) in DMF (10 mL) was stirredat 80° C. overnight. After cooling to room temperature, the mixture waspoured into water (20 mL), and extract with EtOAc (3*30 mL). Thecombined organic layers were washed with water (2*30 mL) and brine (30mL), and concentrated under reduce pressure. The residue was purified bycolumn chromatography on silica gel (MeOH:DCM=5:100) to get the titlecompound (130 mg, 47% yield). LC-MS: m/z 573.2 (M+H)⁺.

Step D1:4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(130 mg, 0.227 mmol) and TBAF (59 mg, 0.227 mmol) in DCM (5 mL) wasstirred at room temperature for 3 h. The mixture was poured into water(20 mL), and the precipitate was filtered. The filter cake was washedwith water (2 mL) and dried to get the title compound (90 mg) as a whitesolid which was used directly in the next step without furtherpurification. LC-MS: m/z 459.1 (M+H)⁺.

Step A:2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)ethylmethanesulfonate

A mixture of4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(250 mg, 0.545 mmol), MsCl (187 mg, 1.636 mmol) and Et₃N (165 mg, 1.636mmol) in DCM (10 mL) was stirred at room temperature for 3 h. Themixture was concentrated in vacuo, and the residue was purified by flashchromatography to afford2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)ethylmethanesulfonate (200 mg) as a white solid. LC-MS: m/z 537.1 (M+H)⁺.

Step B: Compound 353:4-(2-aminoethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)ethylmethanesulfonate (75 mg, 0.14 mmol) in ammonia (7.0 M in MeOH, 10 mL)was stirred at 75° C. in a seal tube for 2 days to afford the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.92 (dd, J=4.03, 1.34 Hz, 1H), 8.34-8.49(m, 3H), 8.18 (dd, J=9.00, 1.75 Hz, 1H), 8.10 (d, J=8.87 Hz, 1H), 7.58(dd, J=8.19, 4.16 Hz, 1H), 7.50 (s, 5H), 7.40 (d, J=2.15 Hz, 2H),7.28-7.35 (m, 3H), 4.01 (br. s., 2H), 2.56 (br. s., 2H). LC-MS: m/z458.0 (M+H)⁺.

Compound 354

Step A:5-chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one

To a mixture of5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one(Synthesized in scheme of Compound 286, 2.29 g, 5.36 mmol), Cs₂CO₃ (3.49g, 10.7 mmol) in DMF (30 mL) was added 1-(chloromethyl)-4-methoxybenzene(0.728 mL). The resultant mixture was stirred at 60° C. for 16 h. Themixture was added into H₂O (30 mL) and extracted with DCM (10 mL*3). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to dryness. The resulting solid was washed with MeOH (5 mL) toget5-chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one(1.6 g) as a white solid. LC-MS: m/z 548.3 (M+H)⁺.

Step B: Compound 354:6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of5-chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one(200 mg, 0.365 mmol), KF (1.7 g, 29 mmol) and 18-Crown-6 (481 mg, 1.825mmol) in NMP (3 mL) was stirred at 180° C. for 4 h under microwaveirradiation in a sealed tube to afford6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.76 (br. s., 1H), 7.53 (d, J=6.98 Hz, 2H),7.26-7.38 (m, 8H), 7.13-7.24 (m, 3H), 6.80 (d, J=8.60 Hz, 3H), 3.76 (s,3H). LC-MS: m/z 488.1 (M+H)⁺.

Compound 355

Step A:6-(4-methoxyphenyl)-5-phenoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 286, 200 mg, 0.45 mmol) and sodiumphenolate (105 mg, 0.9 mmol) in NMP (3 mL) was stirred at 170° C. for 2h under microwave irradiation in a sealed tube to afford6-(4-methoxyphenyl)-5-phenoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.48 (br. s., 2H), 7.42 (br. s., 4H), 7.26-7.37 (m,5H), 7.23 (br. s., 2H), 7.10 (d, J=6.45 Hz, 3H), 6.92 (d, J=7.52 Hz,2H), 3.76 (br. s., 3H). LC-MS: m/z 485.9 (M+H)⁺.

Compound 356

Step A:7-methoxy-6-(4-methoxyphenyl)-N,2,3-triphenylpyrazolo[1,5-a]pyrimidin-5-amine

A suspension of5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine(Synthesized in Scheme of Compound 101, 100 mg, 0.22 mmol), aniline (45mg, 0.48 mmol, 2 eq.), Pd(OAc)₂ (20 mg, 0.09 mmol, 0.1 eq.), Xantphos(26 mg, 0.05 mmol, 0.2 eq.) and Cs₂CO₃ (150 mg, 0.46 mmol, 2 eq.) in1,4-dioxane (5 mL) was stirred at 100° C. for 16 hours under N₂atmosphere. The mixture was filtered through celite, and the filtratewas concentrated in vacuo. The residue was purified by flashchromatography to afford the title compound 2 (70 mg, 64.2% yield) as ayellow solid. LC-MS: m/z 520.7 (M+H)⁺.LC-MS: m/z 499.1 (M+H)⁺.

Step B: Compound 356:6-(4-methoxyphenyl)-2,3-diphenyl-5-(phenylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A solution of 77-methoxy-6-(4-methoxyphenyl)-N,2,3-triphenylpyrazolo[1,5-a]pyrimidin-5-amine(70 mg, 0.14 mmol) in 4M HCl in 1.4-dioxane (3 mL) was stirred at r.t.for 2 hours. Solvent and volatile were removed in vacuo. The mixture wasbasified with NaHCO₃ solution to pH=8 and concentrated in vacuo to givethe the title compound6-(4-methoxyphenyl)-2,3-diphenyl-5-(phenylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹H NMR (DMSO-d₆) δ: 7.41-7.68 (m, 14H), 7.22-7.36 (m, 6H), 4.06 (s, 3H).LC-MS: m/z 484.9 (M+H)⁺.

Compound 358

Step A:6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

A suspension of6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(Synthesized in scheme of Compound 305, 150 mg, 0.29 mmol) and6-methoxypyridin-3-ylboronic acid (133 mg, 0.87 mmol), PdCl₂(dppf) (21mg, 0.03 mmol) and Na₂CO₃ (61 mg, 0.58 mmol) in 1.4-dioxane/water (10mL/1 mL) was stirred and heated to 85° C. for 16 h under N₂ atmosphere.The reaction was then cooled to RT and filtered. The dark filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography, eluting with PE/EA (4/1), to get desired product (40 mg,25% yield) as a white solid. LC-MS: m/z 546.3 (M+H)⁺.

Step B:6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

The mixture of6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one(40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 mL, 5 mmol) was stirredat RT for 1 h to get the desired product.

¹H NMR (DMSO-d₆) δ: 11.47 (br. s., 1H), 8.12 (dd, J=1.6 Hz, 2.8 Hz, 3H),7.67 (dd, J=2.4 Hz, 2.4 Hz, 1H), 7.50-7.40 (m, 3H), 6.90 (d, J=8.0 Hz,1H), 3.90 (s, 3H), 3.08 (t, J=4.8 Hz, 4H), 2.29 (s, 3H), 1.67-1.50 (m,6H). LC-MS: m/z 416.2 (M+H)⁺.

Example 2 Biochemical Assay

In the reaction catalyzed by MAT2A enzyme, L-Met and ATP were convertedto SAM, inorganic phosphate, and inorganic diphosphate. Measurement ofMAT2A enzymatic activity was made by direct chemical detection of theinorganic phosphate upon the addition of sulfuric acid and ammoniummolybdate to the enzymatic reaction mixture, which stoichiometricallyformed highly chromogenic malachite green phosphomolybdate with anabsorption maxima at 620 to 650 nM. The concentration of malachite greenphosphomolybdate produced in the detection reaction is thus directlyrelated to the quantity of product produced by the MAT2A enzyme.Multiple commercial kits exist for this method of phosphate detectionand quantification, such as PiColorLock Gold (Innova Biosciences).

Typical reaction was performed in 50 μl final volume, containing buffer(Tris, pH 8.0, 50 mM KCl, 15 mM MgCl₂, 300 uM EDTA, bovine serum albuminat 0.005% w/v) and 1 μg/ml MAT2A. Compounds were added in 1 μl of DMSOat the desired concentration; a typical dose response curve containedten points with three-fold dilution between compound concentrations. Themixture of MAT2a enzyme and inhibitor was preincubated for 60 minutes at25° C.; the enzymatic reaction was started with the addition of L-Metand ATP to a final concentration of 80 μM and 100 μM respectively. Thereaction was allowed to proceed for 60 minutes at room temperature thenhalted by the addition of 13 μl of PiColor Lock reagent. After a further5 minutes of incubation at room temperature, 5 l of PiColor Stabilizerwas added and the reactions were further incubated at 25° C. for 25minutes. Quantitative measurement of product produced was determined byspectrophotometric analysis at 623 nM and comparison to a phosphatestandard curve.

Recombinant MAT2A protein was expressed in SF9 insect cells and purifiedby metal chelate affinity chromatography, using methods well known inthe art. After expression of His6-tagged MAT2A cells were disrupted by 4passes through an M-Yl 10 Micro fluidizer (Microfluidics) set to 500psi, and then centrifuged at 22,000 rcf for 20 min at 4° C. Thesupernatant was harvested and loaded at 15 cm/h on a Histrap FF 5*1 mlcolumn (GE) which was equilibrated with 50 mM Tris, 500 mM NaCl, pH7.4.Host cell contaminants were removed by washing the column withequilibration buffer followed by equilibration buffer containing 20 mMimidazole and 60 mM imidazole to baseline. MAT2A protein was eluted bythe addition of buffer containing 250 mM imidazole, dialized into 50 mMNaCl, 50 mM Tris, pH 7.4, flash frozen in liquid nitrogen, and stored at−80° C. until use.

Compounds that are shown in Tables 1 and 2 were tested in the foregoingassay and they were determined to inhibit MAT2A with an IC₅₀ accordingto the following scores: (A) less than 100 nM, (B) between 100 nm and 1M, and (C) between 1 μM and 10 M, as shown in Table 3 below.

TABLE 3 Compound No. MAT2A Inhibition Score 101 A 102 A 103 A 104 A 105A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 A 114 A 115 A 116 A 117A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129A 130 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141A 142 A 143 A 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164 A 165A 166 A 167 A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176 A 177A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 215A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A 239A 240 A 241 A 242 A 243 C 244 A 245 A 246 A 247 A 248 A 249 A 250 A 251C 252 A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263A 264 A 265 A 266 A 267 A 268 A 269 A 271 A 272 A 273 A 274 A 275 A 276A 277 A 278 A 279 A 280 A 281 A 282 A 283 A 285 A 286 A 287 A 288 A 290A 291 A 292 A 294 A 295 A 296 A 297 A 298 B 299 B 300 B 301 B 302 B 303C 304 B 305 B 306 C 307 B 308 C 309 B 310 C 311 B 312 B 313 B 314 B 315B 316 B 317 B 318 B 319 B 320 B 321 B 322 C 323 B 324 C 325 B 326 C 327B 328 C 329 B 330 B 331 B 332 B 333 B 334 B 335 B 336 B 337 B 338 B 339B 340 B 346 C 347 C 348 C 349 C 350 C 351 C 352 C 353 C 354 C 355 C 356B 358 A

Example 3 Cellular Assay of Target Engagement (SAM)

Measurement of MAT2A activity in cells was made by direct quantitationof the abundance of the product of its enzymatic activity, SAM. Cancercells were treated with candidate MAT2A inhibitors for a suitableincubation period, and the cells were then lysed using a reagent whichquenched any further enzyme activity. Soluble metabolites including SAMwere collected and SAM itself was directly measured from the lysateusing quantitative LC/MS.

A typical assay was performed using an HCT116 human colon carcinoma cellline which was genetically engineered to delete the MTAP gene(commercially available from Horizon Discovery). This cell line wasutilized because it was determined that loss of the MTAP gene predictssensitivity to MAT2A inhibitors. Cells were plated in 96-well dishes atappropriate cell density. Following 24 hours, cells were then treatedwith the candidate MAT2A inhibitor. Prior to addition to cells, thecompound was first serially diluted in DMSO, typically as a 3-foldserial dilution with 10 dose points. Compound was then transferred to aworking stock plate in cell culture media by adding 5 μl of compound inDMSO to 495 μl of cell culture media. This working stock was then addedto cells via a further 5-fold dilution, by adding 25 μl of working stockto 100 μl of cells in culture media. Following compound addition, cellswere incubated at 37° C./5% CO₂ for 4 hrs.

To quantitate SAM levels following compound treatment, cells were gentlywashed once in Ammonium Carbonate buffer (75 mM at pH 7.4), placed ondry ice, and lysed with metabolite extraction buffer (80% cold methanoland 20% acetic acid containing 50 ng/ml of deuterated d3 SAM). Followingcentrifugation at 4° C. at 3200 rpm for 30 minutes, the supernatant wascollected and stored at −80° C. until analysis by LiquidChromatography-Mass Spectrometry (LC/MS). LC/MS analysis was performedusing an Xevo TQS (Milford, Mass.) operating in positive electrospraymode, with chromatographic separation using a Waters Acquity BEH Amidecolumn. Multiple Reaction Monitoring data was acquired for SAM and thed3SAM standard, using MRM transitions of 399.2/250.1 amu and 402.2/250.1amu, respectively. In a typical LC/MS analysis, the initial flow ratewas 0.5 ml/min of 25% H₂O:ACN(95/5,v/v)-1% FA −10 mM NH₄OAc (MobilePhase A), 75% H₂O:ACN(5/95,v/v)-1% FA −10 mM NH₄OAc (Mobile Phase B), at0.2 min 25% MA, at 0.5 min 65% MA, at 1.1 min 25% MA with a total runtime of 2.5 minutes

Example 4 Assay for Inhibition of Cellular Proliferation

Test compound impact on cancer cell growth was assessed by treatingcancer cells with compound for 4 days and then measuring proliferationusing an ATP-based cell proliferation readout (Cell Titer Glo, PromegaCorporation).

In a typical assay an isogenic pair of HCT116 human colon carcinoma celllines which vary only in MTAP deletion status (HCT116 MTAP+/+ and HCT116MTAP−/−) were plated in 96-well dishes at appropriate cell density.Following 24 hours, cells were then treated with the candidate MAT2Ainhibitor. Prior to addition to cells, the compound was first seriallydiluted in DMSO, typically as a 3-fold serial dilution with 10 dosepoints. Compound was then transferred to a working stock plate in cellculture media by adding 5 μl of compound in DMSO to 495 μl of cellculture media. This working stock was then added to cells via a further5-fold dilution, by adding 25 μl of working stock to 100 μl of cells inculture media. Following compound addition, cells were incubated at 37°C./5% CO₂ for 4 days.

To measure inhibition of cellular proliferation, cells were allowed toequilibrate to room temperature for 30 minutes, and were then treatedwith 125 μl of Cell Titer Glo reagent. The plate was then shaken for 15minutes to ensure complete mixing and full cell lysis. Luminescentsignal of the Cell Titer Glo reagent was then measured using aplate-based luminometer and normalized via an ATP standard curve. Thisluminescence measure was converted to a proliferation index bysubtracting from each datapoint the ATP luminescence measured from acontrol cell plate that was measured at the time of compound treatment(i.e., day 0). Compound activity was then represented as a % change inproliferation relative to a within-plate DMSO control.

We claim:
 1. A method for treating colon carcinoma in a subjectsuffering therefrom, wherein the colon carcinoma is mediated by theoverexpression of MAT2A, or is characterized by a reduction or absenceof methylthioadenosine phosphorylase (MTAP) gene expression, the absenceof the MTAP gene, or reduced function of MTAP protein, comprisingadministering to the subject an effective amount of a compound accordingto formula IA or a pharmaceutically acceptable salt thereof:

wherein: R^(A) is selected from the group consisting of H, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₃-C₁₄-carbocycle,(C₃-C₁₄-carbocyclo)-C₁-C₆-alkyl-, 3- to 14-membered heterocycle orheterocyclo-C₁-C₆-alkyl- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from N, O, or S), (3- to 14-memberedheterocyclo)oxy-, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-,C₆-C₁₄-aryloxy-, —(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R², NR¹R², C(O)NR¹R²,NR¹C(NR²)NR¹R², NR¹C(NR²)(=NR¹), SR¹, —CN, and —OH; wherein each alkyl,alkenyl, alkoxy, aryl, and heterocycle is optionally substituted withone or more substituents selected from the group consisting of R¹, OR¹,halo, —N═N—R¹, NR¹R², —(C₁-C₆-alkyl)NR¹R², —C(O)OR¹, —C(O)NR¹R²,—OC(O)R¹, —CN, —OP(O)(OR¹)₁₋₂, and oxo; R^(B) is selected from the groupconsisting of H, C₂-C₆-alkenyl, and C₁-C₆-alkyl, wherein R^(B) isoptionally substituted by one or more R¹; R^(C), R^(D), and R^(E) areindependently selected from the group consisting of C₃-C₁₄-carbocycle,C₆-C₁₄-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4heterocycle ring members are heteroatoms selected from N, O, or S),wherein R^(C), R^(D), and R^(E) are optionally substituted with one ormore substituents selected from the group consisting of R¹, —OR¹, halo,—NR¹R², —(C₁-C₆-alkyl)-NR¹R², —C(O)OR¹, —C(O)NR¹R², —NO₂, —CN, and oxo;and R¹ and R² are independently selected from the group consisting of H,D (²H), —CN, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₂-C₆-alkynyl, NH₂, —S(O)₀₋₂—(C₁-C₆-alkyl), —S(O)₀₋₂—(C₆-C₁₄-aryl),—C(O)(C₁-C₆-alkyl), —C(O)(C₃-C₁₄-carbocyclo), —C₃-C₁₄-carbocycle,C₆-C₁₄-aryl, and 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from the group consisting of N, O, and S), whereineach alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocyclemoiety of R¹ and R² is optionally substituted with one or moresubstituents selected from the group consisting of hydroxy, halo, —NH₂,—NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH, —C(O)O(C₁-C₆-alkyl),—C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl, —C(O)C₁-C₆-alkyl,—OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃, C₆-C₁₄-aryl,—(C₁-C₆-alkyl)(C₆-C₁₄-aryl), 3- to 14-membered heterocycle orheterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocycle ring members areheteroatoms selected from the group consisting of N, O, and S), and—O(C₆-C₁₄-aryl), or a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein: ring A and ring B are independently a carbocycle or aheterocycle each optionally substituted with one or more substituentsselected from the group consisting of hydroxy, halogen, amino, carboxy,CN, oxo, alkyl, alkoxy and alkylamino, wherein said alkyl, alkoxy andalkylamino are optionally substituted with hydroxy, halogen, amino,carboxy, CN or oxo; ring C is a carbocycle or a heterocycle eachoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl,alkoxy and alkylamino, wherein said alkyl, alkoxy and alkylamino areoptionally substituted with hydroxy, halogen, amino, carboxy, CN or oxo;and R₁ is H or alkyl, a carbocycle or a heterocycle each optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, halogen, amino, NO₂, CN, oxo, carboxy,alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, alkyl, acyl, alkoxy,alkylamino aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy,heteroaryloxy and heteroaralkoxy wherein said alkyl, alkoxy, alkylamino,alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aryl, aralkyl, heteroaryl,heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy areoptionally substituted with hydroxy, halogen, amino, alkylamino,carboxy, CN or oxo.
 2. The method according to claim 1, wherein R^(D)and R^(E) are independently selected from the group consisting ofC₃-C₁₄-carbocycle, C₆-C₁₄-aryl, and 3- to 14-membered heterocycle(wherein 1 to 4 heterocycle ring members are heteroatoms selected fromthe group consisting of N, O, and S).
 3. The method according to claim2, wherein R^(D) and R^(E) are independently selected from the groupconsisting of C₃-C₁₄-carbocycle and C₆-C₁₄-aryl.
 4. The method accordingto claim 3, wherein R^(D) and R^(E) are independently selected from thegroup consisting of C₅-C₇-carbocycle and C₆-C₁₀-aryl.
 5. The methodaccording to claim 4, wherein R^(D) and R^(E) are independently selectedfrom the group consisting of cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, and phenyl.
 6. The method according to claim 5, whereinone of R^(D) and R^(E) is cyclohexyl or cyclohexenyl and the other isphenyl.
 7. The method according to claim 1, wherein R^(A) is selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₃-C₁₄-carbocycle, (C₃-C₁₄-carbocyclo)-C₁-C₆-alkyl-, 3- to 14-memberedheterocycle or heterocyclo(C₁-C₆-alkyl)- (wherein 1 to 4 heterocyclering members are heteroatoms selected from the group consisting of N, O,and S), C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy,—(CH₂)₀₋₆NR¹(CH₂)₀₋₆C(O)R², NR¹R², NR¹C(NR²)NR¹R², —CN, and —OH.
 8. Themethod according to claim 7, wherein R^(A) is selected from the groupconsisting of C₁-C₆-alkyl, —(CH₂)₀₋₆(NR¹(CH₂)₀₋₆)C(O)R², NR¹R², andNR¹C(NR²)NR¹R².
 9. The method according to claim 8, wherein R^(A) isC₁-C₆-alkyl or NR¹R².
 10. The method according to claim 9, wherein R^(A)is NR¹R².
 11. The method according to claim 10, wherein R¹ is H.
 12. Themethod according to claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof is one according to formula IB:

wherein: R^(C) is a C₃-C₁₄-carbocycle or a 3- to 14-membered heterocycle(wherein 1 to 4 heterocycle ring members are heteroatoms selected fromthe group consisting of N, O, and S), each optionally substituted withone or more substituents selected from the group consisting of hydroxy,halogen, —NH₂, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-, carboxy, —CN,oxo, C₁-C₆-alkyl, C₁-C₆-alkoxy, and —NH(C₁-C₆-alkyl), wherein theC₁-C₆-alkyl, C₁-C₆-alkoxy, and NH(C₁-C₆-alkyl) are independently andoptionally substituted with one or more of hydroxy, halogen, —NH₂,carboxy, —CN, or oxo; R^(D) and R^(E) are independently aC₃-C₁₄-carbocycle or a 3- to 14-membered heterocycle (wherein 1 to 4heterocycle ring members are heteroatoms selected from the groupconsisting of N, O, and S), each optionally substituted with one or moresubstituents selected from the group consisting of hydroxy, halogen,—NH₂, C₆-C₁₄-aryl, (C₆-C₁₄-aryl)-C₁-C₆-alkyl-, carboxy, —CN, oxo,C₁-C₆-alkyl, C₁-C₆-alkoxy, and —NH(C₁-C₆-alkyl), wherein theC₁-C₆-alkyl, C₁-C₆-alkoxy, and NH(C₁-C₆-alkyl) are independently andoptionally substituted with one or more of hydroxy, halogen, —NH₂,carboxy, —CN, or oxo; and R¹ is selected from the group consisting of H,C₁-C₆-alkyl, C₃-C₁₄-carbocycle, and 3- to 14-membered heterocycle(wherein 1 to 4 heterocycle ring members are heteroatoms selected fromthe group consisting of N, O, and S), each optionally substituted withone or more substituents selected from the group consisting of hydroxy,halogen, —NH₂, —NO₂, —CN, oxo, carboxy, —C(O)OC₁-C₆-alkyl,(C₁-C₆-alkyl)OC₁-C₆-alkyl-, —C(O)NH₂, C₁-C₆-alkyl, —C(O)H, C₁-C₆-alkoxy,(C₁-C₆-alkyl)N(H)-aryl-, (C₆-C₁₄-aryl)C₁-C₆-alkyl-, 5- to 7-memberedheteroaryl, (5- to 7-membered heteroaryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy,(C₆-C₁₄-aryl)(C₁-C₆-alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5-to 7-membered heteroaryl)(C₁-C₆-alkoxy)-, wherein the C₁-C₆-alkyl,C₁-C₆-alkoxy, (C₁-C₆-alkyl)N(H)—, —C(O)OC₁-C₆-alkyl,(C₁-C₆-alkyl)OC₁-C₆-alkyl-, —C(O)NH₂, C₆-C₁₄-aryl,(C₆-C₁₄-aryl)C₁-C₆-alkyl, 5- to 7-membered heteroaryl, (5- to 7-memberedheteroaryl)-C₁-C₆-alkyl-, C₆-C₁₄-aryloxy, (C₆-C₁₄-aryl)(C₁-C₆-alkoxy)-,(5- to 7-membered heteroaryl)oxy-, and (5- to 7-memberedheteroaryl)(C₁-C₆-alkoxy)- are optionally substituted with one or moreof hydroxy, halogen, —NH₂, (C₁-C₆-alkyl)N(H)—, —COOH, —CN, or oxo,wherein each heteroaryl in R¹ has 1 to 4 heteroaryl ring members thatare heteroatoms selected from the group consisting of N, O, and S. 13.The method according to claim 12, wherein R^(D) is C₃-C₁₄-carbocycleoptionally substituted with one or more members of the group consistingof hydroxy, halogen, —NH₂, —C(O)OH, —CN, oxo, C₁-C₆-alkyl, C₁-C₆-alkoxy,and (C₁-C₆-alkyl)N(H)—, wherein the C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)— are optionally substituted with one or more ofhydroxy, halogen, —NH₂, —C(O)OH, —CN, or oxo.
 14. The method accordingto claim 12, wherein R^(D) is phenyl.
 15. The method according to claim12, wherein R^(D) is cyclohex-1-en-1-yl.
 16. The method according toclaim 12, wherein R^(E) is C₃-C₁₄-carbocycle optionally substituted withone or more members of the group consisting of hydroxy, halogen, —NH₂,—C(O)OH, —CN, oxo, alkyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)—, wherein the C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)— are optionally substituted with one or more ofhydroxy, halogen, —NH₂, —C(O)OH, —CN, or oxo.
 17. The method accordingto claim 12, wherein R^(E) is selected from the group consisting ofcyclohex-1-en-1-yl, (²H₉)cyclohex-1-en-1-yl, cyclohexan-1,3-dien-1-yl,4,4-difluorocyclohex-1-en-1-yl, cyclopent-1-en-1yl, cyclopentyl,pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin-3-yl, pyridin-2-yl,1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl,5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl,1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and3,6-dihydro-2H-pyran-4-yl.
 18. The method according to claim 12, whereinR^(E) is phenyl.
 19. The method according to claim 12, wherein R^(D) iscyclohex-1-en-1-yl.
 20. The method according to claim 12, wherein R^(C)is C₃-C₁₄-carbocycle or 3- to 14-membered heterocycle (wherein 1 to 4heterocycle ring members are heteroatoms selected from the groupconsisting of N, O, and S) and is optionally substituted with one ormore substituents selected from the group consisting of hydroxy,halogen, —NH₂, —C(O)OH, —CN, oxo, C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)—, wherein the C₁-C₆-alkyl, C₁-C₆-alkoxy, and(C₁-C₆-alkyl)N(H)— are optionally substituted with hydroxy, halogen,—NH₂, —C(O)OH, —CN or oxo.
 21. The method according to claim 12, whereinR^(C) is selected from the group consisting of 4-hydroxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-ethoxyphenyl,4-trifluoromethoxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-2-methoxyphenyl, 3,4-dihydroxyphenyl,4-(2,2,2-trifluoroethoxy)phenyl, 4-(2-(dimethylamino)ethoxy)phenyl,3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl,2-chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl,3-amino-4-hydroxyphenyl, 3-amino-4-fluorophenyl,3-(N,N-dimethylaminoethoxy)-4-hydroxyphenyl, 3-chloro-2-hydroxyphenyl,3-hydroxyethoxy-4-hydroxyphenyl,


22. The method according to claim 12, wherein R^(C) is selected from thegroup consisting of 6-methoxypyridin-3-yl, 2-methoxypyridin-4-yl,1H-pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl,2-methoxyquinolin-6-yl, 2-hydroxymethylquinolin-6-yl,3-hydroxy-2-methylquinolin-6-yl, 2-aminoquinazolin-6-yl,4-aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl,2-chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl,3-aminoquinoxalin-6-yl, 3-hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl,imidazo[1,2-a]pyridin-6-yl,


23. The method according to claim 12, wherein R^(C) is 4-methoxyphenyl.24. The method according to claim 12, wherein R¹ is a 3- to 14-memberedheterocycle optionally substituted with one or more substituentsselected from the group consisting of hydroxy, halogen, —NH₂, —NO₂,—C(O)OH, —C(O)OC₁-C₆-alkyl, (C₁-C₆-alkyl)N(H)C(O)—, —CN, oxo,C₁-C₆-alkyl, —C(O)H, C₁-C₆-alkoxy, and (C₁-C₆-alkyl)N(H)—, wherein theC₁-C₆-alkyl, C₁-C₆-alkoxy, (C₁-C₆-alkyl)N(H)—, C(O)OC₁—C₆-alkyl, and(C₁-C₆-alkyl)N(H)C(O)— are optionally substituted with one or more ofhydroxy, halogen, —NH₂, (C₁-C₆-alkyl)N(H)—, —C(O)H, —CN, or oxo.
 25. Themethod according to claim 12, wherein R¹ is selected from the groupconsisting of pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl,1,2,4-triazin-3-yl, each of which is optionally substituted with one ormore of F, Cl, CN, OH, —NO₂, —NH₂, —NHMe, —C(O)NH₂, or methoxy.
 26. Themethod according to claim 12, wherein R¹ is selected from the groupconsisting of:


27. The method according to claim 12, wherein R¹ is selected from thegroup consisting of:


28. The method according to claim 1, wherein the compound or apharmaceutically acceptable salt thereof is selected from the followingtable: 101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

203


29. The method according to claim 1, wherein the compound or apharmaceutically acceptable salt thereof is selected from the followingtable: 204

205

206

207

208

209

210

211

212

213

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

271

272

273

274

275

276

277

278

279

280

281

282

283

285

286

287

288

290

291

292

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

346

347

348

349

350

351

352

353

354

355

356

358


30. The method according to claim 1, wherein the colon carcinoma is MTAPnull.
 31. The method according to claim 30, wherein the colon carcinomahas a KRAS mutation.
 32. The method according to claim 31, wherein theKRAS mutation is an amino acid substitution at residue 12 or
 13. 33. Themethod according to claim 31, wherein the KRAS mutation is G12C, G12R,G12V or G13D.
 34. The method according to claim 1, wherein the coloncarcinoma has a p53 mutation.
 35. The method according to claim 30,wherein the p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H,R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice,R267P, R273C, R282W, A159V or R280K.
 36. The method according to claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 37. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 38. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 39. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 40. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 41. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 42. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.